<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01717898</url>
  </required_header>
  <id_info>
    <org_study_id>UCSF CC#125510</org_study_id>
    <nct_id>NCT01717898</nct_id>
  </id_info>
  <brief_title>A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer</brief_title>
  <official_title>A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Charles Ryan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      There will be two parts to this clinical research study. The purpose of each part is:&#xD;
&#xD;
        -  Phase 1: This part of the study will determine what dose of BEZ235 is safe to give with&#xD;
           a standard dose of abiraterone acetate and prednisone by administering different doses&#xD;
           of BEZ235. This will help to find out what effects, good and/or bad, this combination&#xD;
           has on CRPC.&#xD;
&#xD;
        -  Phase 2: This part of the study will measure the treatment effect of the combination of&#xD;
           BEZ235 and abiraterone acetate/prednisone on CRPC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Prostate Cancer Overview:&#xD;
&#xD;
      Prostate cancer is the second most common cancer in men representing approximately 30% of all&#xD;
      cancers diagnosed in men. When confined to the prostate gland the disease is curable with&#xD;
      local therapy. However approximately 50% of men fail local therapy and develop incurable&#xD;
      metastatic disease. Androgen deprivation (AD) therapy remains the mainstay of treatment, not&#xD;
      only for advanced disease but also in the adjuvant and neo-adjuvant settings. Androgen&#xD;
      deprivation therapy induces a remission in 80 to 90% of patients with advanced disease and&#xD;
      results in a median progression-free survival of 12 to 33 months, at which time an&#xD;
      androgen-independent phenotype usually emerges. This accounts for the median overall survival&#xD;
      of 23 to 37 months from the initiation of androgen deprivation.&#xD;
&#xD;
      Androgen deprivation can be achieved surgically with orchiectomy, or using some form of drug&#xD;
      treatment. Current approaches to AD utilize leutinizing hormone releasing hormone (LHRH)&#xD;
      agonists. These act by continuous stimulation of the anterior pituitary resulting in&#xD;
      inhibition of leutinizing hormone (LH) secretion, and hence a fall in testicular production&#xD;
      of testosterone. Although AD is clinically effective in the majority of patients, studies&#xD;
      have shown that extratesticular sources of testosterone represent an important alternative&#xD;
      source of androgen stimulation in a significant proportion of prostate cancer patients. As&#xD;
      much as 10% of baseline circulating testosterone remains in castrate men, due to the&#xD;
      peripheral conversion of adrenal steroids to testosterone. Increased levels of androgen&#xD;
      receptor confer resistance to antiandrogens in prostate cancer xenograft models. This could&#xD;
      result in amplified signal output from circulating low levels of adrenal androgens and&#xD;
      suggests a role for agents that target the adrenal androgen synthesis pathway.&#xD;
&#xD;
      As prostate cancer progresses to castration-resistant prostate cancer genetic events&#xD;
      accumulate. One of the most consistent genetic findings in CRPC is amplification and&#xD;
      over-expression of the androgen receptor (AR). Multiple groups have demonstrated that&#xD;
      up-regulation of AR expression along with de novo synthesis of androgens by the adrenals&#xD;
      and/or prostate cancer cells themselves is perhaps the most common mechanism by which&#xD;
      prostate cancer cells progress despite castrate levels of circulating testosterone. This&#xD;
      underlying biology is likely the mechanism explaining the recent success of Abiraterone&#xD;
      Acetate.&#xD;
&#xD;
      An important genetic event found to be associated with progression of prostate cancer is loss&#xD;
      of heterozygosity and subsequent homozygous deletion at the 10q23 locus containing the PTEN&#xD;
      tumor suppressor gene. PTEN functions, in part, as a negative regulator of the&#xD;
      phosphatidylinositol 3' (PI3) kinase - AKT pathway. Targeting the PI3K pathway and/or&#xD;
      downstream targets of PI3K has been recognized as an important therapeutic strategy for some&#xD;
      time. An important aspect of PI3K signaling is the PTEN mutation and the downstream events&#xD;
      associated with PI3K signaling are not mutually exclusive with the aforementioned AR&#xD;
      signaling pathway aberrancies that have yielded important therapeutic consequences.&#xD;
      Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, but that&#xD;
      the net effect is antiproliferative and that concomitant anti androgen therapy is&#xD;
      synergistic.&#xD;
&#xD;
      Introduction to BEZ235 and Abiraterone Acetate:&#xD;
&#xD;
      Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, and that&#xD;
      concomitant anti-androgen therapy has synergistic anti-tumor effects with PI3K inhibition.&#xD;
      This study seeks to enhance the efficacy of Abiraterone Acetate in CRPC by concomitantly&#xD;
      targeting PI-3Kinase activity with the novel agent BEZ-235.&#xD;
&#xD;
      BEZ235 is a potent pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor&#xD;
      belonging to the class of imidazoquinoline derivatives. BEZ235 is the investigational agent&#xD;
      utilized in this study.&#xD;
&#xD;
      Abiraterone Acetate is now considered a standard of care for the treatment of Castration&#xD;
      Resistant Prostate Cancer (CRPC) following docetaxel, and is likely to be considered such in&#xD;
      the pre-chemotherapy setting based on recent results. Despite benefits in survival resistance&#xD;
      to this therapy develops in virtually all patients.&#xD;
&#xD;
      Study rationale and purpose:&#xD;
&#xD;
      It is hypothesized that signaling through the PI3Kinase pathway is a major mechanism of&#xD;
      resistance to Abiraterone Acetate therapy (and castration based therapy in general) and that&#xD;
      inhibition of this pathway will enhance the clinical benefit of Abiraterone Acetate.&#xD;
&#xD;
      The addition of BEZ 235 to Abiraterone Acetate provides an opportunity to test if inhibition&#xD;
      of PI3K along with TORC1 will attenuate the survival mechanisms co-opted by CRPC when treated&#xD;
      with Abiraterone Acetate. We will conduct a Phase I study to determine the MTD for this&#xD;
      combination and use that dose for this Phase II study. Biopsies of metastatic disease prior&#xD;
      to and during treatment with BEZ235 plus Abiraterone Acetate will allow for the determination&#xD;
      if mutations in the PTEN and/or PI3kinase axis in biopsied tumors are associated with&#xD;
      response to therapy with the combination of BEZ235 and Abiraterone Acetate.&#xD;
&#xD;
      While PSA decline remains an imperfect surrogate marker for overall survival it remains a&#xD;
      useful means of determining whether a positive clinical &quot;signal&quot; exists for a given treatment&#xD;
      strategy and can be an efficient means of determining if an approach could proceed to more&#xD;
      definitive testing according the standards of the Prostate Cancer Working Group 2 (PCWG2).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Dose limiting toxicities on lowest dose level&#xD;
  </why_stopped>
  <start_date type="Actual">January 31, 2013</start_date>
  <completion_date type="Actual">August 29, 2016</completion_date>
  <primary_completion_date type="Actual">September 3, 2013</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Reported Dose Limiting Toxicities When Combining BEZ235 With Abiraterone Acetate (Phase I).</measure>
    <time_frame>Beginning of study up to 15 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Anti-tumor Responses as Defined by a Decline in PSA of &gt; 50%</measure>
    <time_frame>From day 1 of therapy initiation up to 12 weeks</time_frame>
    <description>Anti-tumor responses as defined by a decline in PSA of &gt; 50% following 12 weeks of therapy to the combination of Abiraterone Acetate plus BEZ-235 occur in a cohort of patients who have received prior therapy with Abiraterone Acetate therapy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Response Proportion as Defined by a Decline in PSA of &gt; 50%</measure>
    <time_frame>From day 1 of therapy initiation up to 12 weeks</time_frame>
    <description>Response proportion as defined by a decline in PSA of &gt; 50% following 12 weeks of therapy for patients treated with the combination of BEZ235 and Abiraterone Acetate plus Prednisone (Phase II outcome measure).&#xD;
Study was terminated during Phase I, Dose level 1 due to toxicity, therefore no Phase II data is available.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose for BEZ235 + Abiraterone Acetate (Phase I).</measure>
    <time_frame>Beginning of study up to 15 months</time_frame>
    <description>Maximum Tolerated Dose (MTD) for BEZ235 + Abiraterone Acetate (to be determined during Phase I). The MTD of BEZ235 will be the dose when given in combination results in less than 33% dose limiting toxicities (DLT).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Trough Concentrations of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination</measure>
    <time_frame>Beginning of study up to 15 months</time_frame>
    <description>Trough concentrations of BEZ235 and Abiraterone Acetate plus Prednisone when used in combination during Phase I.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) in Phase II</measure>
    <time_frame>Beginning of Phase II up to 15 months</time_frame>
    <description>Progression Free Survival (PFS) of the combination of BEZ235 plus Abiraterone Acetate/prednisone as determined by Prostate-Specific Antigen Working Group 2 criteria (PSAWG2 ) during Phase II.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of the Time to PSA Progression in Phase II</measure>
    <time_frame>Beginning of Phase II up to 15 months</time_frame>
    <description>Determination of the time to PSA progression in Phase II based on PSAWG2 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR) in Phase II</measure>
    <time_frame>From beginning of Phase II up to 15 months</time_frame>
    <description>Proportion of patients achieving an objective response to BEZ235 + Abiraterone Acetate/prednisone according to RECIST criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination</measure>
    <time_frame>Beginning of Phase II up to 15 months</time_frame>
    <description>Number of reported Adverse Events in BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase II).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Determination of Whether the Pre-treatment Status of pS6, pAKT, p4EBP1 and PTEN, Determined by IHC in the Optional Biopsies of Metastatic Tumors, Are Associated With Response to BEZ235 Plus Abiraterone Acetate/Prednisone.</measure>
    <time_frame>post study</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Determination of Whether Specific Pathway Changes Are Predictive of Clinical Benefit (Improved PFS) or Resistance Prior to Treatment or During Treatment Using Microarray Analysis.</measure>
    <time_frame>post study</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Castrate-resistant Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Abiraterone/prednisone + BEZ235</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In Phase I, a dose escalation of BEZ235 will be performed using a standard 3 + 3 design to determine the maximum tolerated dose (MTD) of BEZ235 given in combination with continuous fixed doses of Abiraterone Acetate and prednisone. This BEZ235 dose will be used in the phase II portion of the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BEZ235</intervention_name>
    <description>BEZ235 - 200 mg, 300 mg, or 400 mg; po, BID. BEZ235 will be supplied in 200 mg, 300 mg, and 400 mg sachets packaged in boxes.</description>
    <arm_group_label>Abiraterone/prednisone + BEZ235</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.</description>
    <arm_group_label>Abiraterone/prednisone + BEZ235</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Abiraterone acetate</intervention_name>
    <description>1000 mg, po. Abiraterone Acetate is supplied in 250 mg white tablets, four tablets are to be taken with a full glass of water on an empty stomach once daily.</description>
    <arm_group_label>Abiraterone/prednisone + BEZ235</arm_group_label>
    <other_name>CB7630</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients eligible for inclusion in this study have to meet all of the following criteria:&#xD;
&#xD;
          1. Patient has provided a signed study Informed Consent Form prior to any screening&#xD;
             procedure.&#xD;
&#xD;
          2. Patient is ≥ 18 years of age on the day of consenting to the study.&#xD;
&#xD;
          3. Patients must have histologically confirmed adenocarcinoma of the prostate.&#xD;
&#xD;
          4. Radiographic evidence of disease (bone scan, CT scan, ultrasound or MRI acceptable)&#xD;
             that is amenable to image-guided biopsy must be present.&#xD;
&#xD;
          5. Patients must have castrate levels of testosterone (&lt; 50 ng/dL) on GnRH analogues or&#xD;
             have had prior orchiectomy. GnRH analogues must be continued while on study.&#xD;
&#xD;
          6. Progressive disease as demonstrated by a rising PSA or radiographic progression per&#xD;
             PCWG2 criteria.&#xD;
&#xD;
          7. Asymptomatic or minimally symptomatic disease: No use of opiate analgesics (EXCLUDING&#xD;
             codeine or dextromethorphan) for cancer related pain within 28 days of day 1, cycle 1.&#xD;
&#xD;
          8. Phase II Cohort 1: No prior Abiraterone Acetate therapy&#xD;
&#xD;
          9. Phase II Cohort 2: Immediate prior Abiraterone Acetate therapy is required. No&#xD;
             intervening therapy is allowed between Abiraterone Acetate therapy and study therapy.&#xD;
&#xD;
         10. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.&#xD;
&#xD;
         11. Men of reproductive potential who have not had a radical prostatectomy must agree to&#xD;
             use an effective contraceptive method. Patients who have had a prostatectomy are&#xD;
             sterile and do not need to use contraception.&#xD;
&#xD;
         12. Patient has adequate bone marrow and organ function as shown by:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.0 x 109/L&#xD;
&#xD;
               -  Platelets ≥ 100 x 109/L&#xD;
&#xD;
               -  Hemoglobin (Hgb) ≥ 9.0 g/dL&#xD;
&#xD;
               -  INR ≤ 2&#xD;
&#xD;
               -  Serum creatinine ≤ 1.5 x ULN&#xD;
&#xD;
               -  Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a&#xD;
                  total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)&#xD;
&#xD;
               -  AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)&#xD;
&#xD;
               -  Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]&#xD;
&#xD;
               -  HgbA1c ≤8% (Patients with diabetes mellitus not actively being treated and&#xD;
                  patients with an HgbA1c level between 7-8% will be required to have home glucose&#xD;
                  monitoring three times weekly during the first cycle. Patients may also be&#xD;
                  referred to a diabetes specialist as indicated.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients eligible for this study must not meet any of the following criteria:&#xD;
&#xD;
          1. Patient has received previous treatment with PI3K and/or mTOR inhibitors.&#xD;
&#xD;
          2. Phase II Cohort 1: Prior Abiraterone Acetate therapy is an exclusion&#xD;
&#xD;
          3. Prior therapy with any of the following for &gt;1 month: MDV-3100, Orteronel,&#xD;
             ketoconazole or other drugs given with the intention to inhibit CYP 17.&#xD;
&#xD;
          4. Patient has active uncontrolled or symptomatic CNS metastases. Note: A patient with&#xD;
             controlled and asymptomatic CNS metastases may participate in this trial. As such, the&#xD;
             patient must have completed any prior treatment for CNS metastases &gt; 90 days&#xD;
             (including radiotherapy and/or surgery) prior to start of treatment in this study and&#xD;
             should not be receiving chronic corticosteroid therapy for the CNS metastases.&#xD;
&#xD;
          5. Patient has a concurrent malignancy or has had a malignancy in the last 3 years prior&#xD;
             to start of study treatment (with the exception of adequately treated basal or&#xD;
             squamous cell carcinoma or cervical carcinoma in situ).&#xD;
&#xD;
          6. Patient has received wide field radiotherapy (including therapeutic radioisotopes such&#xD;
             as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior&#xD;
             to starting study drug or has not recovered from side effects of such therapy.&#xD;
&#xD;
          7. Patient has had major surgery within 28 days prior to starting study drug or has not&#xD;
             recovered from major side effects of the surgery.&#xD;
&#xD;
          8. Patient has active cardiac disease including any of the following:&#xD;
&#xD;
               -  Left Ventricular Ejection Fraction (LVEF) &lt; 50% as determined by Multiple Gated&#xD;
                  acquisition (MUGA) scan or echocardiogram (ECHO)&#xD;
&#xD;
               -  QTcF &gt; 480 msec on screening ECG&#xD;
&#xD;
               -  Unstable angina pectoris&#xD;
&#xD;
               -  Ventricular arrhythmias except for benign premature ventricular contractions&#xD;
&#xD;
               -  Supraventricular and nodal arrythmias requiring a pacemaker or not controlled&#xD;
                  with medication&#xD;
&#xD;
               -  Conduction abnormality requiring a pacemaker&#xD;
&#xD;
               -  Valvular disease with documented compromise in cardiac function&#xD;
&#xD;
               -  Symptomatic pericarditis&#xD;
&#xD;
          9. Patient has a history of cardiac dysfunction including any of the following:&#xD;
&#xD;
               -  Myocardial infarction within the last 6 months, documented by persistent elevated&#xD;
                  cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF&#xD;
                  function.&#xD;
&#xD;
               -  History of documented congestive heart failure (New York Heart Association&#xD;
                  functional classification III-IV)&#xD;
&#xD;
               -  Documented cardiomyopathy&#xD;
&#xD;
         10. Family history of congenital long or short QT, or known history of QT/QTc prolongation&#xD;
             or Torsades de Pointes (TdP).&#xD;
&#xD;
         11. Patient with medically documented history of active major depressive episodes, bipolar&#xD;
             disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of&#xD;
             suicidal attempt or ideation, or homicidal ideation.&#xD;
&#xD;
         12. Active or uncontrolled infection of hepatitis B or hepatitis C.&#xD;
&#xD;
         13. Inadequately controlled hypertension (i.e., SBP &gt; 180 mmHg or DBP &gt; 100 mmHg).&#xD;
&#xD;
         14. Patient has impairment of gastrointestinal (GI) function or GI disease that may&#xD;
             significantly alter the absorption of BEZ235 (e.g. ulcerative diseases, uncontrolled&#xD;
             nausea, vomiting, diarrhea grade ≥ 2, malabsorption syndrome or small bowel&#xD;
             resection).&#xD;
&#xD;
         15. Use of any chemotherapy, investigational agents, immunotherapy, or hormonal therapy&#xD;
             other LHRH agonists within 28 days of the start of treatment on protocol. Use of bone&#xD;
             targeted agents including bisphosphanates and RANK ligand inhibitors is allowed if on&#xD;
             stable dose; Xgeva or Zometa cannot be started within 28 days of initiating study&#xD;
             therapy.&#xD;
&#xD;
         16. Systemic corticosteroids except as part of on label treatment prostate cancer&#xD;
             regimens.&#xD;
&#xD;
             Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways&#xD;
             diseases), eye drops or local injections (e.g., intra-articular) are allowed.&#xD;
&#xD;
         17. Patient is undergoing active treatment for diabetes mellitus.&#xD;
&#xD;
         18. Patient is being treated at start of study treatment with any of the following drugs:&#xD;
&#xD;
               -  Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4&#xD;
                  including herbal medications (see Appendix 1 for a list of prohibited CYP3A4&#xD;
                  inhibitors and inducers)&#xD;
&#xD;
               -  Drugs with a known risk to induce Torsades de Pointes (see Appendix 3 for a list&#xD;
                  of prohibited drugs)&#xD;
&#xD;
               -  Warfarin and coumadin analogues&#xD;
&#xD;
         19. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pomelos and&#xD;
             exotic citrus fruits (as well as their juices) during the last 7 days prior to start&#xD;
             of treatment. Regular orange juice is permitted.&#xD;
&#xD;
         20. Immunocompromised patients, including known seropositivity for HIV (testing is not&#xD;
             mandatory).&#xD;
&#xD;
         21. Patient has other concurrent severe and/or uncontrolled medical condition that would,&#xD;
             in the investigator's judgment contraindicate his participation in the clinical study&#xD;
             (e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis etc.).&#xD;
&#xD;
         22. Patient is not able to understand or to comply with study instructions and&#xD;
             requirements or has a history of non-compliance to medical regimen.&#xD;
&#xD;
         23. Patients in whom, in the opinion of the treating physician, should receive cytotoxic&#xD;
             chemotherapy with docetaxel.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Charles Ryan, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>October 23, 2012</study_first_submitted>
  <study_first_submitted_qc>October 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 31, 2012</study_first_posted>
  <results_first_submitted>February 27, 2018</results_first_submitted>
  <results_first_submitted_qc>February 27, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">March 27, 2018</results_first_posted>
  <last_update_submitted>February 27, 2018</last_update_submitted>
  <last_update_submitted_qc>February 27, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Charles Ryan</investigator_full_name>
    <investigator_title>Associate Professor of Clinical Medicine &amp; Urology</investigator_title>
  </responsible_party>
  <keyword>Castrate-resistant prostate cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Abiraterone Acetate</mesh_term>
    <mesh_term>Dactolisib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Phase I: BEZ235 200 mg</title>
          <description>Dose level 1:&#xD;
200 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
        </group>
        <group group_id="P2">
          <title>Phase I: BEZ235 300 mg</title>
          <description>Dose level 2:&#xD;
300 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
        </group>
        <group group_id="P3">
          <title>Phase I: BEZ235 400 mg</title>
          <description>Dose level 3:&#xD;
400 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, po.</description>
        </group>
        <group group_id="P4">
          <title>Phase II</title>
          <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="0">Study was terminated during Phase I, Dose level 1 due to toxicity.</participants>
                <participants group_id="P3" count="0">Study was terminated during Phase I, Dose level 1 due to toxicity.</participants>
                <participants group_id="P4" count="0">Study was terminated during Phase I, Dose level 1 due to toxicity.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0">Study was terminated during Phase I, Dose level 1 due to toxicity.</participants>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Abiraterone/Prednisone + BEZ235</title>
          <description>In Phase I, a dose escalation of BEZ235 will be performed using a standard 3 + 3 design to determine the maximum tolerated dose (MTD) of BEZ235 given in combination with continuous fixed doses of Abiraterone Acetate and prednisone. This BEZ235 dose will be used in the phase II portion of the study.&#xD;
BEZ235: BEZ235 - 200 mg, 300 mg, or 400 mg; po, BID. BEZ235 will be supplied in 200 mg, 300 mg, and 400 mg sachets packaged in boxes.&#xD;
Prednisone: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, po. Abiraterone Acetate is supplied in 250 mg white tablets, four tablets are to be taken with a full glass of water on an empty stomach once daily.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="71" lower_limit="59" upper_limit="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Reported Dose Limiting Toxicities When Combining BEZ235 With Abiraterone Acetate (Phase I).</title>
        <time_frame>Beginning of study up to 15 months</time_frame>
        <population>Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I: BEZ235 200 mg</title>
            <description>Dose level 1:&#xD;
200 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O2">
            <title>Phase I: BEZ235 300 mg</title>
            <description>Dose level 2:&#xD;
300 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O3">
            <title>Phase I: BEZ235 400 mg</title>
            <description>Dose level 3:&#xD;
400 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, po.</description>
          </group>
          <group group_id="O4">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Reported Dose Limiting Toxicities When Combining BEZ235 With Abiraterone Acetate (Phase I).</title>
          <population>Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Anti-tumor Responses as Defined by a Decline in PSA of &gt; 50%</title>
        <description>Anti-tumor responses as defined by a decline in PSA of &gt; 50% following 12 weeks of therapy to the combination of Abiraterone Acetate plus BEZ-235 occur in a cohort of patients who have received prior therapy with Abiraterone Acetate therapy</description>
        <time_frame>From day 1 of therapy initiation up to 12 weeks</time_frame>
        <population>Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I: BEZ235 200 mg</title>
            <description>Dose level 1:&#xD;
200 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O2">
            <title>Phase I: BEZ235 300 mg</title>
            <description>Dose level 2:&#xD;
300 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O3">
            <title>Phase I: BEZ235 400 mg</title>
            <description>Dose level 3:&#xD;
400 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, po.</description>
          </group>
          <group group_id="O4">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Anti-tumor Responses as Defined by a Decline in PSA of &gt; 50%</title>
          <description>Anti-tumor responses as defined by a decline in PSA of &gt; 50% following 12 weeks of therapy to the combination of Abiraterone Acetate plus BEZ-235 occur in a cohort of patients who have received prior therapy with Abiraterone Acetate therapy</description>
          <population>Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Response Proportion as Defined by a Decline in PSA of &gt; 50%</title>
        <description>Response proportion as defined by a decline in PSA of &gt; 50% following 12 weeks of therapy for patients treated with the combination of BEZ235 and Abiraterone Acetate plus Prednisone (Phase II outcome measure).&#xD;
Study was terminated during Phase I, Dose level 1 due to toxicity, therefore no Phase II data is available.</description>
        <time_frame>From day 1 of therapy initiation up to 12 weeks</time_frame>
        <population>Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I: BEZ235 200 mg</title>
            <description>Dose level 1:&#xD;
200 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O2">
            <title>Phase I: BEZ235 300 mg</title>
            <description>Dose level 2:&#xD;
300 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O3">
            <title>Phase I: BEZ235 400 mg</title>
            <description>Dose level 3:&#xD;
400 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, po.</description>
          </group>
          <group group_id="O4">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Response Proportion as Defined by a Decline in PSA of &gt; 50%</title>
          <description>Response proportion as defined by a decline in PSA of &gt; 50% following 12 weeks of therapy for patients treated with the combination of BEZ235 and Abiraterone Acetate plus Prednisone (Phase II outcome measure).&#xD;
Study was terminated during Phase I, Dose level 1 due to toxicity, therefore no Phase II data is available.</description>
          <population>Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose for BEZ235 + Abiraterone Acetate (Phase I).</title>
        <description>Maximum Tolerated Dose (MTD) for BEZ235 + Abiraterone Acetate (to be determined during Phase I). The MTD of BEZ235 will be the dose when given in combination results in less than 33% dose limiting toxicities (DLT).</description>
        <time_frame>Beginning of study up to 15 months</time_frame>
        <population>Dose could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I: BEZ235 200 mg</title>
            <description>Dose level 1:&#xD;
200 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O2">
            <title>Phase I: BEZ235 300 mg</title>
            <description>Dose level 2:&#xD;
300 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg PO daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, PO daily</description>
          </group>
          <group group_id="O3">
            <title>Phase I: BEZ235 400 mg</title>
            <description>Dose level 3:&#xD;
400 mg BEZ235 orally (PO) twice a day (BID)&#xD;
Prednisone: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.&#xD;
Abiraterone acetate: 1000 mg, po.</description>
          </group>
          <group group_id="O4">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose for BEZ235 + Abiraterone Acetate (Phase I).</title>
          <description>Maximum Tolerated Dose (MTD) for BEZ235 + Abiraterone Acetate (to be determined during Phase I). The MTD of BEZ235 will be the dose when given in combination results in less than 33% dose limiting toxicities (DLT).</description>
          <population>Dose could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Trough Concentrations of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination</title>
        <description>Trough concentrations of BEZ235 and Abiraterone Acetate plus Prednisone when used in combination during Phase I.</description>
        <time_frame>Beginning of study up to 15 months</time_frame>
        <population>Concentrations could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>BEZ235</title>
            <description>Trough concentration of BEZ235 when used in combination with Abiraterone plus Prednisone.</description>
          </group>
          <group group_id="O2">
            <title>Abiraterone Acetate</title>
            <description>Trough concentration of Abiraterone acetate when used in combination with BEZ235 plus Prednisone.</description>
          </group>
        </group_list>
        <measure>
          <title>Trough Concentrations of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination</title>
          <description>Trough concentrations of BEZ235 and Abiraterone Acetate plus Prednisone when used in combination during Phase I.</description>
          <population>Concentrations could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) in Phase II</title>
        <description>Progression Free Survival (PFS) of the combination of BEZ235 plus Abiraterone Acetate/prednisone as determined by Prostate-Specific Antigen Working Group 2 criteria (PSAWG2 ) during Phase II.</description>
        <time_frame>Beginning of Phase II up to 15 months</time_frame>
        <population>PFS in Phase II could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) in Phase II</title>
          <description>Progression Free Survival (PFS) of the combination of BEZ235 plus Abiraterone Acetate/prednisone as determined by Prostate-Specific Antigen Working Group 2 criteria (PSAWG2 ) during Phase II.</description>
          <population>PFS in Phase II could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Determination of the Time to PSA Progression in Phase II</title>
        <description>Determination of the time to PSA progression in Phase II based on PSAWG2 criteria.</description>
        <time_frame>Beginning of Phase II up to 15 months</time_frame>
        <population>Time to PSA progression could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Determination of the Time to PSA Progression in Phase II</title>
          <description>Determination of the time to PSA progression in Phase II based on PSAWG2 criteria.</description>
          <population>Time to PSA progression could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate (ORR) in Phase II</title>
        <description>Proportion of patients achieving an objective response to BEZ235 + Abiraterone Acetate/prednisone according to RECIST criteria.</description>
        <time_frame>From beginning of Phase II up to 15 months</time_frame>
        <population>ORR could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR) in Phase II</title>
          <description>Proportion of patients achieving an objective response to BEZ235 + Abiraterone Acetate/prednisone according to RECIST criteria.</description>
          <population>ORR could not be determined. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Safety of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination</title>
        <description>Number of reported Adverse Events in BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase II).</description>
        <time_frame>Beginning of Phase II up to 15 months</time_frame>
        <population>No Adverse Events were collected in Phase II. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>Phase II:&#xD;
BEZ235 at MTD&#xD;
Prednisone 5 mg twice daily&#xD;
Abiraterone 1,000 mg daily</description>
          </group>
        </group_list>
        <measure>
          <title>Safety of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination</title>
          <description>Number of reported Adverse Events in BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase II).</description>
          <population>No Adverse Events were collected in Phase II. Study was terminated during Phase I, Dose level 1 due to toxicity.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Determination of Whether the Pre-treatment Status of pS6, pAKT, p4EBP1 and PTEN, Determined by IHC in the Optional Biopsies of Metastatic Tumors, Are Associated With Response to BEZ235 Plus Abiraterone Acetate/Prednisone.</title>
        <time_frame>post study</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Determination of Whether Specific Pathway Changes Are Predictive of Clinical Benefit (Improved PFS) or Resistance Prior to Treatment or During Treatment Using Microarray Analysis.</title>
        <time_frame>post study</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Phase I: Abiraterone/Prednisone + BEZ235 200 mg</title>
          <description>Study was terminated during Phase I, Dose level 1 due to toxicity.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Mucositis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Photosensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Study got terminated due to safety issues.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Charles Ryan, MD</name_or_title>
      <organization>University of California, San Francisco</organization>
      <phone>877-827-3222</phone>
      <email>clinicaltrials@ucsf.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01717898
org study id: UCSF CC#125510
nct id: NCT01717898
lead sponsor: 
collaborator: 
has dmc: Yes
There will be two parts to this clinical research study. The purpose of each part is:

        -  Phase 1: This part of the study will determine what dose of BEZ235 is safe to give with
           a standard dose of abiraterone acetate and prednisone by administering different doses
           of BEZ235. This will help to find out what effects, good and/or bad, this combination
           has on CRPC.

        -  Phase 2: This part of the study will measure the treatment effect of the combination of
           BEZ235 and abiraterone acetate/prednisone on CRPC.
Prostate Cancer Overview:

      Prostate cancer is the second most common cancer in men representing approximately 30% of all
      cancers diagnosed in men. When confined to the prostate gland the disease is curable with
      local therapy. However approximately 50% of men fail local therapy and develop incurable
      metastatic disease. Androgen deprivation (AD) therapy remains the mainstay of treatment, not
      only for advanced disease but also in the adjuvant and neo-adjuvant settings. Androgen
      deprivation therapy induces a remission in 80 to 90% of patients with advanced disease and
      results in a median progression-free survival of 12 to 33 months, at which time an
      androgen-independent phenotype usually emerges. This accounts for the median overall survival
      of 23 to 37 months from the initiation of androgen deprivation.

      Androgen deprivation can be achieved surgically with orchiectomy, or using some form of drug
      treatment. Current approaches to AD utilize leutinizing hormone releasing hormone (LHRH)
      agonists. These act by continuous stimulation of the anterior pituitary resulting in
      inhibition of leutinizing hormone (LH) secretion, and hence a fall in testicular production
      of testosterone. Although AD is clinically effective in the majority of patients, studies
      have shown that extratesticular sources of testosterone represent an important alternative
      source of androgen stimulation in a significant proportion of prostate cancer patients. As
      much as 10% of baseline circulating testosterone remains in castrate men, due to the
      peripheral conversion of adrenal steroids to testosterone. Increased levels of androgen
      receptor confer resistance to antiandrogens in prostate cancer xenograft models. This could
      result in amplified signal output from circulating low levels of adrenal androgens and
      suggests a role for agents that target the adrenal androgen synthesis pathway.

      As prostate cancer progresses to castration-resistant prostate cancer genetic events
      accumulate. One of the most consistent genetic findings in CRPC is amplification and
      over-expression of the androgen receptor (AR). Multiple groups have demonstrated that
      up-regulation of AR expression along with de novo synthesis of androgens by the adrenals
      and/or prostate cancer cells themselves is perhaps the most common mechanism by which
      prostate cancer cells progress despite castrate levels of circulating testosterone. This
      underlying biology is likely the mechanism explaining the recent success of Abiraterone
      Acetate.

      An important genetic event found to be associated with progression of prostate cancer is loss
      of heterozygosity and subsequent homozygous deletion at the 10q23 locus containing the PTEN
      tumor suppressor gene. PTEN functions, in part, as a negative regulator of the
      phosphatidylinositol 3' (PI3) kinase - AKT pathway. Targeting the PI3K pathway and/or
      downstream targets of PI3K has been recognized as an important therapeutic strategy for some
      time. An important aspect of PI3K signaling is the PTEN mutation and the downstream events
      associated with PI3K signaling are not mutually exclusive with the aforementioned AR
      signaling pathway aberrancies that have yielded important therapeutic consequences.
      Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, but that
      the net effect is antiproliferative and that concomitant anti androgen therapy is
      synergistic.

      Introduction to BEZ235 and Abiraterone Acetate:

      Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, and that
      concomitant anti-androgen therapy has synergistic anti-tumor effects with PI3K inhibition.
      This study seeks to enhance the efficacy of Abiraterone Acetate in CRPC by concomitantly
      targeting PI-3Kinase activity with the novel agent BEZ-235.

      BEZ235 is a potent pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor
      belonging to the class of imidazoquinoline derivatives. BEZ235 is the investigational agent
      utilized in this study.

      Abiraterone Acetate is now considered a standard of care for the treatment of Castration
      Resistant Prostate Cancer (CRPC) following docetaxel, and is likely to be considered such in
      the pre-chemotherapy setting based on recent results. Despite benefits in survival resistance
      to this therapy develops in virtually all patients.

      Study rationale and purpose:

      It is hypothesized that signaling through the PI3Kinase pathway is a major mechanism of
      resistance to Abiraterone Acetate therapy (and castration based therapy in general) and that
      inhibition of this pathway will enhance the clinical benefit of Abiraterone Acetate.

      The addition of BEZ 235 to Abiraterone Acetate provides an opportunity to test if inhibition
      of PI3K along with TORC1 will attenuate the survival mechanisms co-opted by CRPC when treated
      with Abiraterone Acetate. We will conduct a Phase I study to determine the MTD for this
      combination and use that dose for this Phase II study. Biopsies of metastatic disease prior
      to and during treatment with BEZ235 plus Abiraterone Acetate will allow for the determination
      if mutations in the PTEN and/or PI3kinase axis in biopsied tumors are associated with
      response to therapy with the combination of BEZ235 and Abiraterone Acetate.

      While PSA decline remains an imperfect surrogate marker for overall survival it remains a
      useful means of determining whether a positive clinical "signal" exists for a given treatment
      strategy and can be an efficient means of determining if an approach could proceed to more
      definitive testing according the standards of the Prostate Cancer Working Group 2 (PCWG2).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Reported Dose Limiting Toxicities When Combining BEZ235 With Abiraterone Acetate (Phase I).
time frame: Beginning of study up to 15 months
measure: Anti-tumor Responses as Defined by a Decline in PSA of > 50%
time frame: From day 1 of therapy initiation up to 12 weeks
description: Anti-tumor responses as defined by a decline in PSA of > 50% following 12 weeks of therapy to the combination of Abiraterone Acetate plus BEZ-235 occur in a cohort of patients who have received prior therapy with Abiraterone Acetate therapy
measure: Response Proportion as Defined by a Decline in PSA of > 50%
time frame: From day 1 of therapy initiation up to 12 weeks
description: Response proportion as defined by a decline in PSA of > 50% following 12 weeks of therapy for patients treated with the combination of BEZ235 and Abiraterone Acetate plus Prednisone (Phase II outcome measure).
Study was terminated during Phase I, Dose level 1 due to toxicity, therefore no Phase II data is available.
measure: Maximum Tolerated Dose for BEZ235 + Abiraterone Acetate (Phase I).
time frame: Beginning of study up to 15 months
description: Maximum Tolerated Dose (MTD) for BEZ235 + Abiraterone Acetate (to be determined during Phase I). The MTD of BEZ235 will be the dose when given in combination results in less than 33% dose limiting toxicities (DLT).
measure: Trough Concentrations of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination
time frame: Beginning of study up to 15 months
description: Trough concentrations of BEZ235 and Abiraterone Acetate plus Prednisone when used in combination during Phase I.
measure: Progression Free Survival (PFS) in Phase II
time frame: Beginning of Phase II up to 15 months
description: Progression Free Survival (PFS) of the combination of BEZ235 plus Abiraterone Acetate/prednisone as determined by Prostate-Specific Antigen Working Group 2 criteria (PSAWG2 ) during Phase II.
measure: Determination of the Time to PSA Progression in Phase II
time frame: Beginning of Phase II up to 15 months
description: Determination of the time to PSA progression in Phase II based on PSAWG2 criteria.
measure: Objective Response Rate (ORR) in Phase II
time frame: From beginning of Phase II up to 15 months
description: Proportion of patients achieving an objective response to BEZ235 + Abiraterone Acetate/prednisone according to RECIST criteria.
measure: Safety of BEZ235 and Abiraterone Acetate Plus Prednisone When Used in Combination
time frame: Beginning of Phase II up to 15 months
description: Number of reported Adverse Events in BEZ235 and Abiraterone Acetate plus Prednisone when used in combination (Phase II).
measure: Determination of Whether the Pre-treatment Status of pS6, pAKT, p4EBP1 and PTEN, Determined by IHC in the Optional Biopsies of Metastatic Tumors, Are Associated With Response to BEZ235 Plus Abiraterone Acetate/Prednisone.
time frame: post study
measure: Determination of Whether Specific Pathway Changes Are Predictive of Clinical Benefit (Improved PFS) or Resistance Prior to Treatment or During Treatment Using Microarray Analysis.
time frame: post study
arm group label: Abiraterone/prednisone + BEZ235
arm group type: Experimental
description: In Phase I, a dose escalation of BEZ235 will be performed using a standard 3 + 3 design to determine the maximum tolerated dose (MTD) of BEZ235 given in combination with continuous fixed doses of Abiraterone Acetate and prednisone. This BEZ235 dose will be used in the phase II portion of the study.
intervention type: Drug
intervention name: BEZ235
description: BEZ235 - 200 mg, 300 mg, or 400 mg; po, BID. BEZ235 will be supplied in 200 mg, 300 mg, and 400 mg sachets packaged in boxes.
arm group label: Abiraterone/prednisone + BEZ235
intervention type: Drug
intervention name: Prednisone
description: 10/mg po daily. Prednisone can be modified at the investigator's discretion, but should not be discontinued.
arm group label: Abiraterone/prednisone + BEZ235
intervention type: Drug
intervention name: Abiraterone acetate
description: 1000 mg, po. Abiraterone Acetate is supplied in 250 mg white tablets, four tablets are to be taken with a full glass of water on an empty stomach once daily.
arm group label: Abiraterone/prednisone + BEZ235
other name: CB7630
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Charles Ryan, MD
role: Study Chair
affiliation: University of California, San Francisco
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Charles Ryan
investigator title: Associate Professor of Clinical Medicine & Urology
mesh term: Prostatic Neoplasms
mesh term: Prednisone
mesh term: Abiraterone Acetate
mesh term: Dactolisib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Study got terminated due to safety issues.
point of contact: 