<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/NCT03834740</url>
  </required_header>
  <id_info>
    <org_study_id>18-500-311-70-38</org_study_id>
    <nct_id>NCT03834740</nct_id>
  </id_info>
  <brief_title>A Phase 0 /II Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Recurrent High-Grade Glioma Patients Scheduled for Resection</brief_title>
  <official_title>A Phase 0/II Study of Ribociclib (LEE011) in Combination With Everolimus in Preoperative Rb-Intact Recurrent High-Grade Glioma Patients Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St. Joseph's Hospital and Medical Center, Phoenix</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ivy Brain Tumor Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Barrow Neurological Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>St. Joseph's Hospital and Medical Center, Phoenix</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical&#xD;
      resection of their tumor. Recurrent GBM patients will be randomized into one of the three&#xD;
      time-interval cohorts for the first two dose levels.&#xD;
&#xD;
      In the lead-in dose escalation study, the first six subjects (lead-in) will receive&#xD;
      ribociclib 400 mg and everolimus 2.5 mg orally-administered in 5 daily doses with the last&#xD;
      dose. If one or less patient experiences DLT among the 6 patients, this regimen with&#xD;
      ribociclib 400 mg and everolimus 2.5mg will be considered safe and we will continue with the&#xD;
      dose escalation phase of the study up to Level 3.&#xD;
&#xD;
      Four dose escalation levels:&#xD;
&#xD;
      Level 0: ribociclib 400mg and everolimus 2.5&#xD;
&#xD;
      Level 1: ribociclib 600mg and everolimus 2.5mg&#xD;
&#xD;
      Level 2: ribociclib 600mg and everolimus 5mg&#xD;
&#xD;
      Level 3: ribociclib 600mg and everolimus 10mg&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 21, 2018</start_date>
  <completion_date type="Actual">February 18, 2022</completion_date>
  <primary_completion_date type="Actual">February 18, 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic analysis -Total and Unbound Ribociclib and Everolimus AUC (0-24)</measure>
    <time_frame>Pre, 0.5, 1, 2, 4, 7, 24 hours post the last dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic analysis - Total and Unbound Ribociclib and Everolimus Median concentration Cmax (0-24)</measure>
    <time_frame>Pre, 0.5, 1, 2, 4, 7, 24 hours post the last dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic analysis -Median concentration of Total Ribociclib and Everolimus Tmax</measure>
    <time_frame>0-24 hours after the last dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic analysis - Total Ribociclib and Everolimus T1/2 (0-24)</measure>
    <time_frame>0-24 hours after the last dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic analysis - Total and Unbound Ribociclib and Everolimus CL/F (0-24)</measure>
    <time_frame>0-24 hours after the last dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Median concentration of ribociclib and everolimus for all patients for unbound plasma, CSF, Unbound NE, Unbound enhancing (2-24H post last dose)</measure>
    <time_frame>2-24 hours after the last dose</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>The percentage of pRB positive cells will be quantified in resected post-treatment recurrent tumor tissue compared to baseline (archival primary GBM tumor)</measure>
    <time_frame>Intraoperatively</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>The percentage of pS6 positive cells will be quantified in resected post-treatment recurrent tumor tissue compared to baseline (archival primary GBM tumor)</measure>
    <time_frame>Intraoperatively</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>MTD: highest dose of drug that did not cause a DLT in &gt; 33% of participants</measure>
    <time_frame>From the date of the first dose given until the second documented DLT, assessed up to 24 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Median progression-free survival (PFS) from time of surgery to date of recurrence in Phase 2 patients</measure>
    <time_frame>From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival (OS) from time of surgery to date of recurrence in Phase 2 patients</measure>
    <time_frame>From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse Events</measure>
    <time_frame>Through study completion, assessed up to 60 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median concentration of trough plasma concentrations of Total Ribociclib and Total Everolimus in Phase 2</measure>
    <time_frame>From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>The median percentage of CDK4/6 and mTOR pathway active cells compared to baseline (total and phosphorylated forms of Rb, FoxM1, S6, 4EBP, as well as cleaved Caspase-3 and MIB1. Expression of Cyclin D1, Cyclin E1, PI3K/mTOR signaling components)</measure>
    <time_frame>baseline to intraoperative</time_frame>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Glioblastoma Multiforme</condition>
  <condition>Glioma of Brain</condition>
  <arm_group>
    <arm_group_label>Cohort 1: last dose 1 to 3 hours prior to resection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:&#xD;
• Cohort 1: last ribociclib+everolimus dose 1 to 3 hours prior to craniotomy for tumor resection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2: last dose 7 to 9 hours prior to resection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:&#xD;
• Cohort 2: last ribociclib+everolimus dose 7 to 9 hours prior to craniotomy for tumor resection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3: last dose 23 to 25 hours prior to resection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:&#xD;
• Cohort 3: last ribociclib+everolimus dose 23 to 25 hours prior to craniotomy for tumor resection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ribociclib</intervention_name>
    <description>Ribociclib administered orally in 5 daily doses prior to resection</description>
    <arm_group_label>Cohort 1: last dose 1 to 3 hours prior to resection</arm_group_label>
    <arm_group_label>Cohort 2: last dose 7 to 9 hours prior to resection</arm_group_label>
    <arm_group_label>Cohort 3: last dose 23 to 25 hours prior to resection</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>Everolimus administered orally in 5 daily doses prior to resection</description>
    <arm_group_label>Cohort 1: last dose 1 to 3 hours prior to resection</arm_group_label>
    <arm_group_label>Cohort 2: last dose 7 to 9 hours prior to resection</arm_group_label>
    <arm_group_label>Cohort 3: last dose 23 to 25 hours prior to resection</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Prior resection of histologically-diagnosed WHO Grade III or IV glioma. A. Glioma&#xD;
             patients who have progressed on or following standard (Stupp regimen) therapy, which&#xD;
             included maximal surgical resection, temozolomide, and fractionated radiotherapy.&#xD;
&#xD;
          2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or&#xD;
             contrast-enhanced MRI.&#xD;
&#xD;
          3. Subjects must have measurable disease preoperatively, defined as at least 1&#xD;
             contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per&#xD;
             RANO criteria.&#xD;
&#xD;
          4. For gliomas, archival tissue must demonstrate: (a) RB positivity (≥20%) on&#xD;
             immunohistochemistry OR no RB mutations on next-generation sequencing (NGS), (b)&#xD;
             Chromosomal loss of CDKN2A/B/C OR CDK4/6 or CCND1/2 amplification on array CGH, (c)&#xD;
             mTOR+: PTEN loss OR PIK3C2B or AKT3 amplification on aCGH OR mutations for PIK3CA or&#xD;
             PIK3R1, or mTOR or PTEN mutations using rhAMP analysis or pS6 positivity on&#xD;
             immunohistochemistry (≥10% for pS6). If mutations within the mTOR/PI3K pathways cannot&#xD;
             be accurately detected due to poor tissue quality the enrollment criteria will be&#xD;
             determined using RB and pS6 positivity.&#xD;
&#xD;
          5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Appendix 1)&#xD;
&#xD;
          6. Patients ≥ 18 years of age&#xD;
&#xD;
          7. Ability to understand and the willingness to sign a written informed consent document.&#xD;
             (personally or by the legally authorized representative, if applicable).&#xD;
&#xD;
          8. Patient has voluntarily agreed to participate by giving written informed&#xD;
             consent.(personally or by the legally authorized representative, if applicable).&#xD;
&#xD;
             (Written informed consent for the protocol must be obtained prior to any screening&#xD;
             procedures. If consent cannot be expressed in writing, it must be formally documented&#xD;
             and witnessed, ideally via an independent trusted witness.)&#xD;
&#xD;
          9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory&#xD;
             tests and other procedures.&#xD;
&#xD;
         10. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or&#xD;
             patient has had a hysterectomy.&#xD;
&#xD;
         11. Patient has adequate bone marrow and organ function as defined by the following&#xD;
             laboratory values (as assessed by the local laboratory for eligibility):&#xD;
&#xD;
             The following laboratory criteria have been met:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (recommended)&#xD;
&#xD;
               -  Hemoglobin (Hgb) ≥ 9.0 g/dL&#xD;
&#xD;
               -  Platelets ≥ 100 x 109/L&#xD;
&#xD;
               -  Potassium, total calcium (corrected for serum albumin), magnesium, sodium, and&#xD;
                  phosphorus within normal limits for the institution or corrected to within normal&#xD;
                  limits with supplements before first dose of study medication.&#xD;
&#xD;
               -  INR ≤1.5 (unless the patient is receiving anticoagulants and the INR is within&#xD;
                  the therapeutic range of intended use for that anticoagulant within 7 days prior&#xD;
                  to the first dose of study drug)&#xD;
&#xD;
               -  Serum creatinine &lt; 1.5 mg/dL&#xD;
&#xD;
               -  Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min.&#xD;
&#xD;
               -  In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate&#xD;
                  aminotransferase (AST) &lt; 2.5 x ULN.&#xD;
&#xD;
               -  Serum total bilirubin &lt;ULN, or &lt; 3.0 x ULN in patients with well-documented&#xD;
                  Gilbert's syndrome.&#xD;
&#xD;
               -  Serum cholesterol &lt; 300 mg/dL or &lt; 7.75 mmol/L AND triclycerides &lt; 2.5 x ULN&#xD;
                  (NOTE: in case one or both of these thresholds are exceeded, the patient can only&#xD;
                  be included after initiation of appropriate lipid lowering medication.)&#xD;
&#xD;
         12. QTcF interval at screening &lt; 450 msec [using Fridericia's correction (formula =&#xD;
             QT/(RR)0.33)]&#xD;
&#xD;
         13. Resting heart rate 50-90 bpm (may be repeated up to 2x)&#xD;
&#xD;
         14. Must be able to swallow ribociclib and everolimus capsules/tablets&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients eligible must not meet any of the following criteria:&#xD;
&#xD;
          1. Archival tissue is not available for research use or there is not a sufficient&#xD;
             quantity available to confirm eligibility.&#xD;
&#xD;
          2. Archival tumor is not Rb-positive status and mTOR-positive status&#xD;
&#xD;
          3. Patient has not received prior radiotherapy&#xD;
&#xD;
          4. Co-morbid condition(s) that, at the opinion of the investigator, prevent safe surgical&#xD;
             treatment&#xD;
&#xD;
          5. Active infection or fever &gt; 38.5°C&#xD;
&#xD;
          6. Active (acute or chronic) or uncontrolled severe infection, liver disease such as&#xD;
             cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.&#xD;
             quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)&#xD;
&#xD;
          7. Known severely impaired lung function (spirometry and DLCO 50% or less of normal and&#xD;
             O2 saturation 88% or less at rest on room air)&#xD;
&#xD;
          8. Active, bleeding diathesis&#xD;
&#xD;
          9. Patients with known hypersensitivity to any of the excipients of ribociclib or mTOR&#xD;
             inhibitors (sirolimus or everolimus), including peanut, soy and lactose&#xD;
&#xD;
         10. Patients with a clinically significant hypersensitivity to everolimus or to other&#xD;
             rapamycin derivatives.&#xD;
&#xD;
         11. Prior therapy with ribociclib or any CDK4/6 inhibitor (e.g. palbociclib, abemaciclib),&#xD;
             or with everolimus&#xD;
&#xD;
         12. Patient who has received radiotherapy ≤4 weeks or limited field radiation for&#xD;
             palliation ≤2 weeks prior to starting study drug, and who has not recovered to grade 1&#xD;
             or better from related side effects of such therapy (exceptions include alopecia or&#xD;
             other toxicities not considered a safety risk for the patient at investigator's&#xD;
             discretion) and/or in whom ≥25% of the bone marrow (Ellis, 1961) was irradiated&#xD;
&#xD;
         13. Patient has a concurrent malignancy or malignancy within 3 years prior to starting&#xD;
             study drug, with the exception of adequately treated, basal or squamous cell&#xD;
             carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer&#xD;
&#xD;
         14. Patient has impairment of gastrointestinal (GI) function or GI disease that may&#xD;
             significantly alter the absorption of the study drugs (e.g., ulcerative diseases,&#xD;
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel&#xD;
             resection)&#xD;
&#xD;
         15. Patient has a known history of HIV infection (seropositivity; testing not mandatory)&#xD;
&#xD;
         16. Patients who have received live attenuated vaccines within 1 week of start of&#xD;
             everolimus and during the study. Patient should also avoid close contact with others&#xD;
             who have received live attenuated vaccines. Examples of live attenuated vaccines&#xD;
             include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever,&#xD;
             varicella and TY21a typhoid vaccines&#xD;
&#xD;
         17. Patient has any other concurrent severe and/or uncontrolled medical condition that&#xD;
             would, in the investigator's judgment, cause unacceptable safety risks, contraindicate&#xD;
             patient participation in the clinical study or compromise compliance with the protocol&#xD;
             (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled&#xD;
             fungal, bacterial or viral infections, etc.)&#xD;
&#xD;
         18. Uncontrolled diabetes mellitus as defined by HbA1c &gt;8% despite adequate therapy as&#xD;
             indicated by the medical history. Patients with a known history of impaired fasting&#xD;
             glucose or diabetes mellitus (DM) may be included, however blood glucose and&#xD;
             antidiabetic treatment must be monitored closely throughout the trial and adjusted as&#xD;
             necessary&#xD;
&#xD;
         19. Clinically significant, uncontrolled heart disease and/or cardiac repolarization&#xD;
             abnormalities, including any of the following:&#xD;
&#xD;
               -  History of acute coronary syndromes (including myocardial infarction, unstable&#xD;
                  angina pectoris, coronary artery bypass grafting, coronary angioplasty, or&#xD;
                  stenting) or symptomatic pericarditis within 6 months prior to screening.&#xD;
&#xD;
               -  History of documented congestive heart failure (New York Heart Association&#xD;
                  functional classification III-IV).&#xD;
&#xD;
               -  Documented cardiomyopathy&#xD;
&#xD;
               -  Left Ventricular Ejection Fraction (LVEF) &lt;50% as determined by Multiple Gated&#xD;
                  acquisition (MUGA) scan or echocardiogram (ECHO) at screening&#xD;
&#xD;
               -  Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),&#xD;
                  complete left bundle branch block, high-grade AV block (e.g. bifascicular block,&#xD;
                  Mobitz type II and third-degree AV block).&#xD;
&#xD;
               -  Long QT syndrome or family history of idiopathic sudden death or congenital long&#xD;
                  QT syndrome, or any of the following:&#xD;
&#xD;
               -  Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or&#xD;
                  hypomagnesemia, history of cardiac failure, or history of clinically&#xD;
                  significant/symptomatic bradycardia.&#xD;
&#xD;
               -  Concomitant use of medication(s) with a known risk to prolong the QT interval&#xD;
                  and/or known to cause Torsades de Pointe that cannot be discontinued (within 5&#xD;
                  half-lives or 7 days prior to starting study drug) or replaced by safe&#xD;
                  alternative medication&#xD;
&#xD;
               -  Inability to determine the QT interval on screening (QTcF, using Fridericia's&#xD;
                  correction)&#xD;
&#xD;
               -  Systolic blood pressure (SBP) &gt;160 mmHg or &lt;90 mmHg at screening (may be repeated&#xD;
                  up to 2x).&#xD;
&#xD;
         20. Patient is currently receiving any of the following medications and cannot be&#xD;
             discontinued 7 days prior to starting study drug (see Appendix 2 for details):&#xD;
&#xD;
               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit&#xD;
                  hybrids, pummelos, star-fruit, pomegranates or pomegranate juice and Seville&#xD;
                  oranges&#xD;
&#xD;
               -  That have a narrow therapeutic window and are predominantly metabolized through&#xD;
                  CYP3A4/5&#xD;
&#xD;
               -  Herbal preparations/medications, dietary supplements known as strong inhibitors&#xD;
                  or inducers of CYP3A4 or those with a known risk of QT prolongation. (Does not&#xD;
                  include Ca, Mg, Vit D or KCl supplements)&#xD;
&#xD;
               -  Known strong inhibitors or inducers of P-gp&#xD;
&#xD;
         21. Patients taking ACE inhibitors&#xD;
&#xD;
         22. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for&#xD;
             treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight&#xD;
             heparin (LMWH) or fondaparinux is allowed&#xD;
&#xD;
         23. Participation in a prior investigational study within 30 days prior to enrollment or&#xD;
             within 5 half-lives of the investigational product, whichever is longer&#xD;
&#xD;
         24. Patient has had major surgery within 14 days prior to starting study drug or has not&#xD;
             recovered from major side effects (tumor biopsy is not considered as major surgery)&#xD;
&#xD;
         25. Patient has not recovered from all toxicities related to prior anticancer therapies to&#xD;
             NCI-CTCAE version 4.03 Grade ≤2 (Exception to this criterion: patients with any grade&#xD;
             of alopecia and amenorrhea are allowed to enter the study)&#xD;
&#xD;
         26. Patient with a Child-Pugh score B or C&#xD;
&#xD;
         27. Patient has a history of non-compliance to medical regimen or inability to grant&#xD;
             consent&#xD;
&#xD;
         28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a&#xD;
             female after conception and until the termination of gestation, confirmed by a&#xD;
             positive hCG laboratory test.]&#xD;
&#xD;
         29. Women of child-bearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant, unwilling to use highly effective methods of contraception during&#xD;
             dosing and for 3 months after the last dose of study treatment. Highly effective&#xD;
             contraception methods include:&#xD;
&#xD;
               -  Total abstinence (when this is in line with the preferred and usual lifestyle of&#xD;
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,&#xD;
                  post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
                  contraception&#xD;
&#xD;
               -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.&#xD;
                  In case of oophorectomy alone, only when the reproductive status of the woman has&#xD;
                  been confirmed by follow up hormone level assessment&#xD;
&#xD;
               -  Male sterilization (at least 6 months prior to screening) with the appropriate&#xD;
                  post-vasectomy documentation of the absence of sperm in the ejaculate. For female&#xD;
                  subjects on the study the vasectomized male partner should be the sole partner&#xD;
                  for that subject&#xD;
&#xD;
               -  Use of oral, injected or implanted hormonal methods of contraception or placement&#xD;
                  of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of&#xD;
                  hormonal contraception that have comparable efficacy (failure rate &lt;1%), for&#xD;
                  example hormone vaginal ring or transdermal hormone contraception&#xD;
&#xD;
               -  In case of use of oral contraception, women should have been stable on the same&#xD;
                  pill for a minimum of 3 months before taking study treatment&#xD;
&#xD;
               -  Note: Oral contraceptives are allowed but should be used in conjunction with a&#xD;
                  barrier method of contraception due to unknown effect of drug-drug interaction&#xD;
                  Women are considered post-menopausal and not of child bearing potential if they&#xD;
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate&#xD;
                  clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had&#xD;
                  surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation&#xD;
                  at least six weeks ago. In the case of oophorectomy alone, only when the&#xD;
                  reproductive status of the woman has been confirmed by follow up hormone level&#xD;
                  assessment is she considered not of child bearing potential&#xD;
&#xD;
         30. Sexually active males unwilling to use a condom during intercourse while taking drug&#xD;
             and for 21 days after stopping treatment and should not father a child in this period.&#xD;
             A condom is required to be used also by vasectomized men in order to prevent delivery&#xD;
             of the drug via seminal fluid.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nader Sanai, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Deputy Director of the Ivy Brain Tumor Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Chandler Regional Medical Center</name>
      <address>
        <city>Chandler</city>
        <state>Arizona</state>
        <zip>85224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph's Hospital and Medical Center</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HonorHealth Scottsdale Osborn Medical Center</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85251</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>January 30, 2019</study_first_submitted>
  <study_first_submitted_qc>February 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</study_first_posted>
  <last_update_submitted>January 11, 2023</last_update_submitted>
  <last_update_submitted_qc>January 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>recurrent GBM</keyword>
  <keyword>brain tumor</keyword>
  <keyword>GBM</keyword>
  <keyword>glioma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Glioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03834740
org study id: 18-500-311-70-38
nct id: NCT03834740
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
In the proposed trial, patients will be administered ribociclib+everolimus prior to surgical
      resection of their tumor. Recurrent GBM patients will be randomized into one of the three
      time-interval cohorts for the first two dose levels.

      In the lead-in dose escalation study, the first six subjects (lead-in) will receive
      ribociclib 400 mg and everolimus 2.5 mg orally-administered in 5 daily doses with the last
      dose. If one or less patient experiences DLT among the 6 patients, this regimen with
      ribociclib 400 mg and everolimus 2.5mg will be considered safe and we will continue with the
      dose escalation phase of the study up to Level 3.

      Four dose escalation levels:

      Level 0: ribociclib 400mg and everolimus 2.5

      Level 1: ribociclib 600mg and everolimus 2.5mg

      Level 2: ribociclib 600mg and everolimus 5mg

      Level 3: ribociclib 600mg and everolimus 10mg
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Pharmacokinetic analysis -Total and Unbound Ribociclib and Everolimus AUC (0-24)
time frame: Pre, 0.5, 1, 2, 4, 7, 24 hours post the last dose
measure: Pharmacokinetic analysis - Total and Unbound Ribociclib and Everolimus Median concentration Cmax (0-24)
time frame: Pre, 0.5, 1, 2, 4, 7, 24 hours post the last dose
measure: Pharmacokinetic analysis -Median concentration of Total Ribociclib and Everolimus Tmax
time frame: 0-24 hours after the last dose
measure: Pharmacokinetic analysis - Total Ribociclib and Everolimus T1/2 (0-24)
time frame: 0-24 hours after the last dose
measure: Pharmacokinetic analysis - Total and Unbound Ribociclib and Everolimus CL/F (0-24)
time frame: 0-24 hours after the last dose
measure: Median concentration of ribociclib and everolimus for all patients for unbound plasma, CSF, Unbound NE, Unbound enhancing (2-24H post last dose)
time frame: 2-24 hours after the last dose
measure: The percentage of pRB positive cells will be quantified in resected post-treatment recurrent tumor tissue compared to baseline (archival primary GBM tumor)
time frame: Intraoperatively
measure: The percentage of pS6 positive cells will be quantified in resected post-treatment recurrent tumor tissue compared to baseline (archival primary GBM tumor)
time frame: Intraoperatively
measure: MTD: highest dose of drug that did not cause a DLT in > 33% of participants
time frame: From the date of the first dose given until the second documented DLT, assessed up to 24 months
measure: Median progression-free survival (PFS) from time of surgery to date of recurrence in Phase 2 patients
time frame: From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
measure: Median Overall Survival (OS) from time of surgery to date of recurrence in Phase 2 patients
time frame: From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
measure: Number of Adverse Events
time frame: Through study completion, assessed up to 60 months
measure: Median concentration of trough plasma concentrations of Total Ribociclib and Total Everolimus in Phase 2
time frame: From date of the first Phase 2 dose until the first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
measure: The median percentage of CDK4/6 and mTOR pathway active cells compared to baseline (total and phosphorylated forms of Rb, FoxM1, S6, 4EBP, as well as cleaved Caspase-3 and MIB1. Expression of Cyclin D1, Cyclin E1, PI3K/mTOR signaling components)
time frame: baseline to intraoperative
arm group label: Cohort 1: last dose 1 to 3 hours prior to resection
arm group type: Experimental
description: Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:
• Cohort 1: last ribociclib+everolimus dose 1 to 3 hours prior to craniotomy for tumor resection
arm group label: Cohort 2: last dose 7 to 9 hours prior to resection
arm group type: Experimental
description: Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:
• Cohort 2: last ribociclib+everolimus dose 7 to 9 hours prior to craniotomy for tumor resection
arm group label: Cohort 3: last dose 23 to 25 hours prior to resection
arm group type: Experimental
description: Three to fourteen patients will receive ribociclib and everolimus orally-administered in 5 daily doses with the last dose being administered at one of 3 intervals before brain tumor resection:
• Cohort 3: last ribociclib+everolimus dose 23 to 25 hours prior to craniotomy for tumor resection
intervention type: Drug
intervention name: Ribociclib
description: Ribociclib administered orally in 5 daily doses prior to resection
arm group label: Cohort 1: last dose 1 to 3 hours prior to resection
arm group label: Cohort 2: last dose 7 to 9 hours prior to resection
arm group label: Cohort 3: last dose 23 to 25 hours prior to resection
intervention type: Drug
intervention name: Everolimus
description: Everolimus administered orally in 5 daily doses prior to resection
arm group label: Cohort 1: last dose 1 to 3 hours prior to resection
arm group label: Cohort 2: last dose 7 to 9 hours prior to resection
arm group label: Cohort 3: last dose 23 to 25 hours prior to resection
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nader Sanai, MD
role: Principal Investigator
affiliation: Deputy Director of the Ivy Brain Tumor Center
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Everolimus
sharing ipd: Undecided