<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/NCT03837821</url>
  </required_header>
  <id_info>
    <org_study_id>1710018693</org_study_id>
    <nct_id>NCT03837821</nct_id>
  </id_info>
  <brief_title>(CLONEVO): Cell cycLe inhbitiON to Target the EVolution of UrOthelial Cancer</brief_title>
  <acronym>CLONEVO</acronym>
  <official_title>A Window-of-opportunity Trial of Abemaciclib Followed by Radical Cystectomy in Patients With Platinum-ineligible Urothelial Carcinoma to Evaluate CDK4/6-dependent Phosphorylation of Pocket Proteins and Clonal Evolution Dynamics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Weill Medical College of Cornell University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eli Lilly and Company</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Weill Medical College of Cornell University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Single-arm, open-label window-of-opportunity trial of neoadjuvant Abemaciclib in 20 patients,&#xD;
      with tumor tissue obtained as standard of care at tumor resection (pre-Abemaciclib) and&#xD;
      cystectomy (post-Abemaciclib)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A Window-of-Opportunity Trial of Abemaciclib followed by radical cystectomy in patients with&#xD;
      Platinum-Ineligible Urothelial Carcinoma to Evaluate CDK4/6-Dependent Phosphorylation of&#xD;
      Pocket Proteins and Clonal Evolution Dynamics. Subjects will be treated with Abemaciclib at&#xD;
      200 mg every 12 hours for at least 4 weeks (and likely slightly longer depending upon&#xD;
      surgical date). Individual dose reductions will be made on the basis of the AEs observed. In&#xD;
      the absence of treatment delays due to adverse event(s), treatment will be continued until&#xD;
      the surgical date unless any of the following criteria applies: 1-Disease progression;&#xD;
      2-Intercurrent illness that prevents further administration of treatment; 3-Unacceptable&#xD;
      adverse event(s) as a result of Abemaciclib; 4- Patient decides to withdraw from the study;&#xD;
      5-General or specific changes in the patient's condition render the patient unacceptable for&#xD;
      further treatment in the judgment of the investigator. Patients will be followed with&#xD;
      history, physical, and blood tests at each visit to monitor for toxicity. Patients will be&#xD;
      followed for survival endpoints following completion of this study for 3 years after surgery&#xD;
      or until death. Patients removed from study for unacceptable adverse events will be followed&#xD;
      until resolution or stabilization of the adverse event.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 5, 2019</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>Early Phase 1</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>Change in cell-cycle dynamics between pre- and post-Abemaciclib tumor samples</measure>
    <time_frame>At baseline and post 4 week treatment</time_frame>
    <description>Cell-cycle dynamics will be assessed by immunohistochemistry of tumor tissues, circulating tumor DNA (ctDNA) blood samples.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events (TEAEs) of Abemaciclib</measure>
    <time_frame>At baseline through 3 year follow up</time_frame>
    <description>TEAEs will be assessed by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect on tumor downstaging defined as &lt;pT2 at time of cystectomy</measure>
    <time_frame>At baseline and post 4 week treatment</time_frame>
    <description>Tumor downstaging will be assess from tissue collected at the time of cystectomy.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Impact of Abemaciclib on clonal evolution</measure>
    <time_frame>Initiation of treatment up to 3 years</time_frame>
    <description>Clonal evolution will be assessed by whole-exome sequencing and RNA sequencing</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Bladder Cancer</condition>
  <arm_group>
    <arm_group_label>All Subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Abemaciclib 200 mg oral, every 12 hours</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Abemaciclib</intervention_name>
    <description>Abemaciclib 200 mg oral, every 12 hours</description>
    <arm_group_label>All Subjects</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Age ≥ 18 years old at time of informed consent&#xD;
&#xD;
          2. Histologically confirmed MIBC (T2-T4) pure or mixed histology urothelial carcinoma&#xD;
             [urothelial carcinoma should be the dominant (&gt;50%) histology].&#xD;
&#xD;
          3. Refusing cisplatin-based chemotherapy or ineligible for cisplatin-based chemotherapy&#xD;
             due to at least one of the following:&#xD;
&#xD;
               1. Creatinine clearance &lt; 60 mL/min (by Cockcroft-Gault calculation and/or measured&#xD;
                  creatinine clearance)&#xD;
&#xD;
               2. Hearing loss ≥ grade 2 by CTCAE criteria and/or;&#xD;
&#xD;
               3. Neuropathy ≥ grade 2 by CTCAE criteria and/or&#xD;
&#xD;
               4. Heart failure NYHA ≥ III&#xD;
&#xD;
          4. Medically fit for TURBT and radical cystectomy&#xD;
&#xD;
          5. Adequate organ and marrow function as defined below:&#xD;
&#xD;
               1. Absolute neutrophil count ≥ 1.5 K/mm3&#xD;
&#xD;
               2. White blood cell count (WBC) &gt; 3.0 K/mm3&#xD;
&#xD;
               3. Platelets ≥ 100 K/mm3&#xD;
&#xD;
               4. Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
               5. Serum total bilirubin ≤ 1.5 x ULN (Patients with Gilbert's syndrome with a total&#xD;
                  bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted)&#xD;
&#xD;
               6. ALT and AST ≤ 3.0 x ULN&#xD;
&#xD;
          6. Ability to swallow oral medications&#xD;
&#xD;
          7. Patients who received radiotherapy must have completed and fully recovered from the&#xD;
             acute effects of radiotherapy. A washout period of at least 14 days is required&#xD;
             between end of radiotherapy and randomization&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Patients with locally advanced unresectable or metastatic urothelial carcinoma as&#xD;
             assessed on baseline radiographic imaging obtained within from the date of signed&#xD;
             consent, 28 days prior to study enrollment. Low volume (&lt;1.5 cm) suspicious lymph node&#xD;
             metastases in the pelvis are allowed if they are in the LN dissection template field.&#xD;
             The required radiographic imaging includes:&#xD;
&#xD;
               1. Abdomen/pelvis - CT/MRI&#xD;
&#xD;
               2. Chest - chest x-ray or CT scan&#xD;
&#xD;
               3. Bone scan or FDG-PET/CT in the presence of bone pain or unexplained elevated&#xD;
                  alkaline phosphatase&#xD;
&#xD;
          2. Patients with another active second malignancy other than non-melanoma skin cancers&#xD;
             and localized prostate cancer. Patients that have completed all necessary therapy and&#xD;
             are considered to be &lt;30% risk of relapse are not considered to have an active second&#xD;
             malignancy and are eligible for enrollment.&#xD;
&#xD;
          3. Patients who have received anti-cancer therapy including chemotherapy, radiotherapy,&#xD;
             immunotherapy, and monoclonal antibodies ≤ 4 weeks or 5 half-lives, whichever is&#xD;
             longer, prior to starting study drug. Patients who received chemotherapy must have&#xD;
             recovered to CTCAE Grade ≤1 from the acute effects of chemotherapy except for residual&#xD;
             alopecia or Grade 2 peripheral neuropathy prior to Cycle 1 Day 1. Patients currently&#xD;
             enrolled in any other type of medical research (for example: medical device) judged by&#xD;
             the sponsor not to be scientifically or medically compatible with this study are also&#xD;
             excluded.&#xD;
&#xD;
          4. Patients who have serious and/or uncontrolled preexisting medical condition(s) that,&#xD;
             in the judgment of the investigator, would preclude participation in this study (for&#xD;
             example, interstitial lung disease, severe dyspnea at rest or requiring oxygen&#xD;
             therapy, severe renal impairment [e.g. estimated creatinine clearance &lt;30ml/min],&#xD;
             history of major surgical resection involving the stomach or small bowel, or&#xD;
             preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition&#xD;
             resulting in baseline Grade 2 or higher diarrhea).&#xD;
&#xD;
          5. Patients who have had major surgery within 14 days prior to Cycle 1 Day 1.&#xD;
&#xD;
          6. Have an active bacterial infection (especially if requiring IV antibiotics), systemic&#xD;
             fungal and/or known viral infection (for example, human immunodeficiency virus&#xD;
             antibodies, hepatitis B surface antigen, or hepatitis C antibodies).&#xD;
&#xD;
          7. Subjects who received a strong CYP3A inhibitor within 7 days prior to the first dose&#xD;
             of study drug, or patients who require continuous treatment with a strong CYP3A&#xD;
             inhibitor&#xD;
&#xD;
          8. The patient has a personal history of any of the following conditions: syncope of&#xD;
             cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but&#xD;
             not limited to, ventricular tachycardia and ventricular fibrillation), or sudden&#xD;
             cardiac arrest.&#xD;
&#xD;
          9. Pregnant or breast-feeding women&#xD;
&#xD;
         10. Women who do not agree to use a medically approved contraceptive method during the&#xD;
             treatment period and for 3 weeks following the last dose of Abemaciclib&#xD;
&#xD;
         11. Men who do not agree to use a reliable method of birth control and to not donate sperm&#xD;
             during the study and for at least 3 months following the last dose of Abemaciclib&#xD;
&#xD;
         12. Subjects unwilling or unable to comply with the protocol&#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>Bishoy Faltas, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Weill Medical College of Cornell University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>GUONC Research Team</last_name>
    <phone>646-962-2072</phone>
    <email>guonc@med.cornell.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <investigator>
      <last_name>Roger Li, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Rohit Jain, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>NewYork-Presbyterian Brooklyn Methodist Hospital</name>
      <address>
        <city>Brooklyn</city>
        <state>New York</state>
        <zip>11217</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>John Graham, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Weill Cornell Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>GUONC Research Team</last_name>
      <phone>646-962-2072</phone>
      <email>guonc@med.cornell.edu</email>
    </contact>
    <investigator>
      <last_name>Bishoy Faltas, M.D</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UT Southwestern Medical Center - Simmons Comprehensive Cancer Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Amy Rowell</last_name>
      <phone>214-648-7001</phone>
      <email>mailto:Amy.Rowell@utsouthwestern.edu</email>
    </contact>
    <investigator>
      <last_name>Suzanne Cole, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>February 6, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>July 25, 2023</last_update_submitted>
  <last_update_submitted_qc>July 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03837821
org study id: 1710018693
nct id: NCT03837821
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Single-arm, open-label window-of-opportunity trial of neoadjuvant Abemaciclib in 20 patients,
      with tumor tissue obtained as standard of care at tumor resection (pre-Abemaciclib) and
      cystectomy (post-Abemaciclib)
A Window-of-Opportunity Trial of Abemaciclib followed by radical cystectomy in patients with
      Platinum-Ineligible Urothelial Carcinoma to Evaluate CDK4/6-Dependent Phosphorylation of
      Pocket Proteins and Clonal Evolution Dynamics. Subjects will be treated with Abemaciclib at
      200 mg every 12 hours for at least 4 weeks (and likely slightly longer depending upon
      surgical date). Individual dose reductions will be made on the basis of the AEs observed. In
      the absence of treatment delays due to adverse event(s), treatment will be continued until
      the surgical date unless any of the following criteria applies: 1-Disease progression;
      2-Intercurrent illness that prevents further administration of treatment; 3-Unacceptable
      adverse event(s) as a result of Abemaciclib; 4- Patient decides to withdraw from the study;
      5-General or specific changes in the patient's condition render the patient unacceptable for
      further treatment in the judgment of the investigator. Patients will be followed with
      history, physical, and blood tests at each visit to monitor for toxicity. Patients will be
      followed for survival endpoints following completion of this study for 3 years after surgery
      or until death. Patients removed from study for unacceptable adverse events will be followed
      until resolution or stabilization of the adverse event.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in cell-cycle dynamics between pre- and post-Abemaciclib tumor samples
time frame: At baseline and post 4 week treatment
description: Cell-cycle dynamics will be assessed by immunohistochemistry of tumor tissues, circulating tumor DNA (ctDNA) blood samples.
measure: Incidence of Treatment-Emergent Adverse Events (TEAEs) of Abemaciclib
time frame: At baseline through 3 year follow up
description: TEAEs will be assessed by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
measure: Effect on tumor downstaging defined as <pT2 at time of cystectomy
time frame: At baseline and post 4 week treatment
description: Tumor downstaging will be assess from tissue collected at the time of cystectomy.
measure: Impact of Abemaciclib on clonal evolution
time frame: Initiation of treatment up to 3 years
description: Clonal evolution will be assessed by whole-exome sequencing and RNA sequencing
arm group label: All Subjects
arm group type: Experimental
description: Abemaciclib 200 mg oral, every 12 hours
intervention type: Drug
intervention name: Abemaciclib
description: Abemaciclib 200 mg oral, every 12 hours
arm group label: All Subjects
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bishoy Faltas, MD
role: Principal Investigator
affiliation: Weill Medical College of Cornell University
last name: GUONC Research Team
phone: 646-962-2072
email: guonc@med.cornell.edu
facility: 
status: Not yet recruiting
investigator: 
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Urinary Bladder Neoplasms
sharing ipd: No