<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/NCT03774446</url>
  </required_header>
  <id_info>
    <org_study_id>Pro52406</org_study_id>
    <secondary_id>FD-R-6106</secondary_id>
    <nct_id>NCT03774446</nct_id>
  </id_info>
  <brief_title>Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease</brief_title>
  <official_title>A Phase 2 Multicenter Study of Seliciclib (R-roscovitine) for Cushing Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cedars-Sinai Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cedars-Sinai Medical Center</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>
      This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4&#xD;
      weeks of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing&#xD;
      disease.&#xD;
&#xD;
      Funding Source - FDA Office of Orphan Products Development (OOPD)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of oral&#xD;
      seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to&#xD;
      13 subjects will be treated with 80 mg each day for 4 weeks. The study will also evaluate&#xD;
      effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 2, 2018</start_date>
  <completion_date type="Anticipated">August 2025</completion_date>
  <primary_completion_date type="Anticipated">August 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <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 participants with a normalized 24-hour urinary free cortisol (UFC) at study completion</measure>
    <time_frame>4 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with UFC above the upper limit of normal (ULN) but reduced by ≥50% from baseline at study completion</measure>
    <time_frame>4 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma adrenocorticotrophic hormone</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Salivary cortisol</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum cortisol</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glycated hemoglobin (HbA1c)</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting blood glucose</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weight and height to report body mass index (BMI) in kg/m^2</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on visual field exam</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in tumor size on pituitary MRI</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in quality of life measured using the CushingQOL questionnaire</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of treatment-emergent adverse events graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 4.0</measure>
    <time_frame>Baseline and week 4</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">13</enrollment>
  <condition>Cushing Disease</condition>
  <arm_group>
    <arm_group_label>Seliciclib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>80 mg each day oral seliciclib for 4 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Seliciclib</intervention_name>
    <description>Drug: Seliciclib</description>
    <arm_group_label>Seliciclib</arm_group_label>
    <other_name>R-roscotivine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female patients at least 18 years old&#xD;
&#xD;
          -  Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH)&#xD;
             production:&#xD;
&#xD;
               -  Persistent hypercortisolemia established by two consecutive 24-hour UFC&#xD;
                  assessment ≥1.5× the upper limit of normal&#xD;
&#xD;
               -  Normal or elevated ACTH levels&#xD;
&#xD;
               -  Pituitary adenoma (&gt;1 cm) on MRI or inferior petrosal sinus sampling (IPSS)&#xD;
                  central to peripheral ACTH gradient &gt;2 at baseline and &gt;3 after CRH stimulation&#xD;
&#xD;
               -  Recurrent or persistent CD defined as pathologically confirmed resected pituitary&#xD;
                  ACTH-secreting tumor or IPSS central to peripheral ACTH gradient &gt;2 at baseline&#xD;
                  and &gt;3 after CRH stimulation, and 24h-UFC &gt;ULN beyond post-surgical week 6&#xD;
&#xD;
          -  Patients on medical treatment for Cushing disease. The following washout periods must&#xD;
             be completed before screening assessments are performed:&#xD;
&#xD;
               -  Inhibitors of steroidogenesis: metyrapone, ketoconazole: 2 weeks;&#xD;
                  Levoketoconazole: 3 weeks; osilodrostat: 6 weeks&#xD;
&#xD;
               -  Somatostatin receptor ligand pasireotide: short-acting, 2 weeks; long-acting, 4&#xD;
                  weeks&#xD;
&#xD;
               -  Progesterone receptor antagonist mifepristone: 2 weeks&#xD;
&#xD;
               -  Dopamine agonist cabergoline: 4 weeks&#xD;
&#xD;
               -  Patients treated with CYP3A or CYP2B6 strong inducers or inhibitors, including&#xD;
                  those listed below. Required washout time varies between drugs; minimum 5-6 times&#xD;
                  the half-life of the drug.&#xD;
&#xD;
                    -  Strong CYP3A inducers: apalutamide, carbamazepine, enzalutamide, mitotane,&#xD;
                       phenytoin, rifampin, St. John's wort&#xD;
&#xD;
                    -  Moderate CYP3A inducers: bosentan, efavirenz, etravirine, phenobarbital,&#xD;
                       primidone&#xD;
&#xD;
                    -  Weak CYP3A inducers: armodafinil, modafinil, rufinamide&#xD;
&#xD;
                    -  Strong CYP2B6 inducer: carbamazepine&#xD;
&#xD;
                    -  Moderate CYP2B6 inducers: efavirenz, rifampin&#xD;
&#xD;
                    -  Weak CYP2B6 inducers: nevirapine, ritonavir&#xD;
&#xD;
                    -  Strong CYP3A inhibitors: boceprevir, cobicistat, danoprevir and ritonavir,&#xD;
                       elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir,&#xD;
                       itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and&#xD;
                       ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir,&#xD;
                       saquinavir and ritonavir, telaprevir, tipranavir and ritonavir,&#xD;
                       telithromycin, troleandomycin, voriconazole, clarithromycin, idelalisib,&#xD;
                       nefazodone, nelfinavir.&#xD;
&#xD;
                    -  Moderate CYP3A inhibitors: aprepitant, ciprofloxacin, conivaptan,&#xD;
                       crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole,&#xD;
                       fluvoxamine, imatinib, verapamil&#xD;
&#xD;
                    -  Strong CYP2B6 inhibitor: ticlopidine&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Patients with compromised visual fields, and not stable for at least 6 months&#xD;
&#xD;
          -  Patients with abutment or compression of the optic chiasm on MRI and normal visual&#xD;
             fields&#xD;
&#xD;
          -  Patients with Cushing's syndrome due to non-pituitary ACTH secretion&#xD;
&#xD;
          -  Patients with hypercortisolism secondary to adrenal tumors or nodular (primary)&#xD;
             bilateral adrenal hyperplasia&#xD;
&#xD;
          -  Patients who have a known inherited syndrome as the cause for hormone over secretion&#xD;
             (i.e., Carney Complex, McCune-Albright syndrome, Multiple endocrine neoplasia (MEN) 1&#xD;
&#xD;
          -  Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)&#xD;
&#xD;
          -  Patients with cyclic Cushing's syndrome defined by any measurement of UFC over the&#xD;
             previous 1 months within normal range&#xD;
&#xD;
          -  Patients with pseudo-Cushing's syndrome, i.e., non-autonomous hypercortisolism due to&#xD;
             overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolled&#xD;
             depression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, and&#xD;
             uncontrolled diabetes mellitus&#xD;
&#xD;
          -  Patients who have undergone major surgery within 1 month prior to screening&#xD;
&#xD;
          -  Patients with serum K+&lt; 3.5 while on replacement treatment&#xD;
&#xD;
          -  Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C &gt;8%&#xD;
&#xD;
          -  Patients who have clinically significant impairment in cardiovascular function or are&#xD;
             at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV),&#xD;
             unstable angina, sustained ventricular tachycardia, clinically significant&#xD;
             bradycardia, high grade atrioventricular (AV) block, history of acute MI less than one&#xD;
             year prior to study entry&#xD;
&#xD;
          -  Patients with liver disease or history of liver disease such as cirrhosis, chronic&#xD;
             active hepatitis B and C, or chronic persistent hepatitis, or patients with abnormal&#xD;
             alanine transferase (ALT) or aspartate aminotransferase (AST) at screening or patients&#xD;
             with advanced liver fibrosis (≥10 kPa) on elastography at screening&#xD;
&#xD;
          -  Patients with estimated glomerular filtration rate (eGFR) &lt;45 mL/min/1.73 m2&#xD;
&#xD;
          -  Patients not biochemically euthyroid&#xD;
&#xD;
          -  Patients who have any current or prior medical condition that can interfere with the&#xD;
             conduct of the study or the evaluation of its results, such as&#xD;
&#xD;
               -  History of immunocompromise, including a positive HIV test result (ELISA and&#xD;
                  Western blot). An HIV test will not be required, however, previous medical&#xD;
                  history will be reviewed&#xD;
&#xD;
               -  Presence of active or suspected acute or chronic uncontrolled infection&#xD;
&#xD;
               -  History of, or current alcohol misuse/abuse in the 12 month period prior to&#xD;
                  screening&#xD;
&#xD;
          -  Female patients who are pregnant or lactating, or are of childbearing potential and&#xD;
             not practicing a medically acceptable method of birth control. If a woman is&#xD;
             participating in the trial then one form of contraception is sufficient (pill or&#xD;
             diaphragm) and the partner should use a condom. If oral contraception is used in&#xD;
             addition to condoms, the patient must have been practicing this method for at least&#xD;
             two months prior to screening and must agree to continue the oral contraceptive&#xD;
             throughout the course of the study and for 3 months after the study has ended. Male&#xD;
             patients who are sexually active are required to use condoms during the study and for&#xD;
             three months afterwards as a precautionary measure (available data do not suggest any&#xD;
             increased reproductive risk with the study drugs)&#xD;
&#xD;
          -  Patients who have participated in any clinical investigation with an investigational&#xD;
             drug within 1 month prior to screening or patients who have previously been treated&#xD;
             with seliciclib&#xD;
&#xD;
          -  Patients with any ongoing or likely to require additional concomitant medical&#xD;
             treatment to treat CD&#xD;
&#xD;
          -  Patients who have received pituitary irradiation within the last 5 years prior to the&#xD;
             baseline visit&#xD;
&#xD;
          -  Patients who have been treated with radionuclide at any time prior to study entry&#xD;
&#xD;
          -  Patients with known hypersensitivity to seliciclib&#xD;
&#xD;
          -  Patients with a history of non-compliance to medical regimens or who are considered&#xD;
             potentially unreliable or will be unable to complete the entire study&#xD;
&#xD;
          -  Patients with hepatitis B surface antigen (HbsAg) positivity&#xD;
&#xD;
          -  Patients with hepatitis C antibody (anti-HCV) positivity&#xD;
&#xD;
          -  Patients with prolonged QTcF on screening electrocardiogram (QTcF &gt;450 msec)&#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>Shlomo Melmed, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ning-Ai Liu, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Vivian Hwe</last_name>
    <phone>424-315-4489</phone>
    <email>vivian.hwe@cshs.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vivian Hwe</last_name>
      <phone>424-315-4489</phone>
      <email>vivian.hwe@cshs.org</email>
    </contact>
    <investigator>
      <last_name>Shlomo Melmed, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ning-Ai Liu, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Liu NA, Araki T, Cuevas-Ramos D, Hong J, Ben-Shlomo A, Tone Y, Tone M, Melmed S. Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease. J Clin Endocrinol Metab. 2015 Jul;100(7):2557-64. doi: 10.1210/jc.2015-1606. Epub 2015 May 5.</citation>
    <PMID>25942479</PMID>
  </reference>
  <reference>
    <citation>Liu NA, Jiang H, Ben-Shlomo A, Wawrowsky K, Fan XM, Lin S, Melmed S. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8414-9. doi: 10.1073/pnas.1018091108. Epub 2011 May 2.</citation>
    <PMID>21536883</PMID>
  </reference>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>November 6, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 13, 2018</study_first_posted>
  <last_update_submitted>September 10, 2023</last_update_submitted>
  <last_update_submitted_qc>September 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cedars-Sinai Medical Center</investigator_affiliation>
    <investigator_full_name>Shlomo Melmed, MD</investigator_full_name>
    <investigator_title>Sr. Vice President of Academic Affairs</investigator_title>
  </responsible_party>
  <keyword>Cushing disease</keyword>
  <keyword>R-roscovitine</keyword>
  <keyword>Seliciclib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>ACTH-Secreting Pituitary Adenoma</mesh_term>
    <mesh_term>Pituitary ACTH Hypersecretion</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Roscovitine</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03774446
org study id: Pro52406
secondary id: FD-R-6106
nct id: NCT03774446
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4
      weeks of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing
      disease.

      Funding Source - FDA Office of Orphan Products Development (OOPD)
This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of oral
      seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to
      13 subjects will be treated with 80 mg each day for 4 weeks. The study will also evaluate
      effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with a normalized 24-hour urinary free cortisol (UFC) at study completion
time frame: 4 weeks
measure: Number of participants with UFC above the upper limit of normal (ULN) but reduced by ≥50% from baseline at study completion
time frame: 4 weeks
measure: Plasma adrenocorticotrophic hormone
time frame: Baseline and week 4
measure: Salivary cortisol
time frame: Baseline and week 4
measure: Serum cortisol
time frame: Baseline and week 4
measure: Glycated hemoglobin (HbA1c)
time frame: Baseline and week 4
measure: Fasting blood glucose
time frame: Baseline and week 4
measure: Weight and height to report body mass index (BMI) in kg/m^2
time frame: Baseline and week 4
measure: Blood pressure
time frame: Baseline and week 4
measure: Change on visual field exam
time frame: Baseline and week 4
measure: Change in tumor size on pituitary MRI
time frame: Baseline and week 4
measure: Change in quality of life measured using the CushingQOL questionnaire
time frame: Baseline and week 4
measure: Number of treatment-emergent adverse events graded using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 4.0
time frame: Baseline and week 4
arm group label: Seliciclib
arm group type: Experimental
description: 80 mg each day oral seliciclib for 4 weeks
intervention type: Drug
intervention name: Seliciclib
description: Drug: Seliciclib
arm group label: Seliciclib
other name: R-roscotivine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Shlomo Melmed, MD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
last name: Ning-Ai Liu, MD, PhD
role: Study Director
affiliation: Cedars-Sinai Medical Center
last name: Vivian Hwe
phone: 424-315-4489
email: vivian.hwe@cshs.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United States
citation: Liu NA, Araki T, Cuevas-Ramos D, Hong J, Ben-Shlomo A, Tone Y, Tone M, Melmed S. Cyclin E-Mediated Human Proopiomelanocortin Regulation as a Therapeutic Target for Cushing Disease. J Clin Endocrinol Metab. 2015 Jul;100(7):2557-64. doi: 10.1210/jc.2015-1606. Epub 2015 May 5.
PMID: 25942479
citation: Liu NA, Jiang H, Ben-Shlomo A, Wawrowsky K, Fan XM, Lin S, Melmed S. Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8414-9. doi: 10.1073/pnas.1018091108. Epub 2011 May 2.
PMID: 21536883
responsible party type: Principal Investigator
investigator affiliation: Cedars-Sinai Medical Center
investigator full name: Shlomo Melmed, MD
investigator title: Sr. Vice President of Academic Affairs
mesh term: ACTH-Secreting Pituitary Adenoma
mesh term: Pituitary ACTH Hypersecretion
mesh term: Roscovitine