<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/NCT01719861</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-25491</org_study_id>
    <secondary_id>VAR0087</secondary_id>
    <nct_id>NCT01719861</nct_id>
  </id_info>
  <brief_title>Phase 2a Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors</brief_title>
  <official_title>A Phase 2a Intrapatient Dose Escalation Study of Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Joel Neal</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Intrapatient dose escalation study of desipramine in subjects with small cell lung cancer&#xD;
      (SCLC) and other high-grade neuroendocrine tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants will start desipramine by mouth nightly (QHS) for 6 weeks, with weekly dose&#xD;
      escalation. Starting dose will be 25 to 75 mg. The desipramine dose will be escalated until&#xD;
      the maximum dose of 450 mg is reached or a maximum safe dose per subject is established.&#xD;
&#xD;
      Dose level may be adjusted (decreased) based on cardiac or general adverse effects.&#xD;
      desipramine level will be tapered if the subject experience disease progression, unless&#xD;
      physician judges immediate suspension is in the subjects best interest.&#xD;
&#xD;
      Assessments will be conducted every 28 days, and will include ECGs, physicians and blood&#xD;
      samples.&#xD;
&#xD;
      One partial and/or complete response will be sufficient to consider a larger clinical trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Lack of efficacy&#xD;
  </why_stopped>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2014</primary_completion_date>
  <phase>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>Overall Response Rate (ORR)</measure>
    <time_frame>6 weeks</time_frame>
    <description>Overall response rate (ORR) was assessed as the number of patients who achieve either a partial (PR) or complete response (CR) measured by CT scans and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria, divided by the total number of patients treated on the study. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Desipramine Maximum Dose</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>Assessed as the median per patient maximum dose (MD) using intra-patient dose escalation, and reported as the highest dose of desipramine administered continuously for 1 week or greater.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Serum Desipramine Levels During Treatment</measure>
    <time_frame>Up to 6 weeks</time_frame>
    <description>Median serum desipramine levels during treatment is reported as the median of the maximum steady state serum concentration observed in all patients.&#xD;
Therapeutic concentration of desipramine is 100 to 300 ng/mL, and toxic concentration is &gt; 300 ng/mL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS), Median</measure>
    <time_frame>Up to 5 years from enrollment to radiographic progression or drug discontinuation</time_frame>
    <description>Median PFS was defined as the time from randomization to disease progression (or death if the patient died before progression) calculated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival (OS)</measure>
    <time_frame>From start of enrollment until death, no limit</time_frame>
    <description>Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Small Cell Lung Cancer (SCLC)</condition>
  <condition>Neuroendocrine Tumors</condition>
  <arm_group>
    <arm_group_label>Desipramine HCl</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Desipramine is a tricyclic antidepressant (TCA).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Desipramine HCL</intervention_name>
    <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. The target dose level at 6 weeks is 450 mg (maximum dosage) or the maximum tolerated dose (MTD) for each subject.</description>
    <arm_group_label>Desipramine HCl</arm_group_label>
    <other_name>Norpramin</other_name>
    <other_name>Pertofrane</other_name>
    <other_name>Desmethylimipramine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Metastatic small-cell lung cancer&#xD;
&#xD;
          -  Metastatic high-grade neuroendocrine carcinoma of any organ system (high-grade defined&#xD;
             by Ki-67 ≥ 20% and/or ≥ 20 mitoses/10 (HPF).&#xD;
&#xD;
          -  Received at least one line of prior chemotherapy treatment for metastatic disease.&#xD;
&#xD;
          -  Daily chemotherapy must be completed ≥ 2 weeks prior to registration&#xD;
&#xD;
          -  Weekly chemotherapy must be completed ≥ 2 weeks prior to registration&#xD;
&#xD;
          -  Chemotherapy every 2 weeks must be completed ≥ 3 weeks prior to registration&#xD;
&#xD;
          -  Chemotherapy every 3 weeks must be completed ≥ 4 weeks prior to registration&#xD;
&#xD;
          -  ECOG Performance Status 0 to 2&#xD;
&#xD;
          -  Measurable disease by RECIST 1.1 criteria&#xD;
&#xD;
          -  Age at least 18 years&#xD;
&#xD;
          -  Estimated life expectancy at least 3 months&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1,500/ mm³&#xD;
&#xD;
          -  Platelets ≥ 100,000/mm³&#xD;
&#xD;
          -  Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
          -  Total bilirubin ≤ 1.5 mg/dL, OR ≤ 2 X ULN if tumor involves the liver&#xD;
&#xD;
          -  AST(SGOT)&#xD;
&#xD;
          -  ALT(SGPT) ≤ 3 X ULN&#xD;
&#xD;
          -  Creatinine ≤ 1.5 X ULN&#xD;
&#xD;
          -  Creatinine clearance ≥ 45 mL/min/1.73m²) for patients with creatinine levels above&#xD;
             institutional normal&#xD;
&#xD;
          -  QT interval corrected using Fridericia's method (QTcF) &lt; 450 msec (males) or &lt; 470&#xD;
             msec (females)&#xD;
&#xD;
          -  PR &lt; 240 msec&#xD;
&#xD;
          -  QRS &lt; 100 msec&#xD;
&#xD;
          -  Brain metastases must be asymptomatic and have been adequately treated with radiation&#xD;
             finishing at least 1 week prior to initiation of study treatment.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Clinically-significant ventricular arrhythmia including cardiac arrest&#xD;
&#xD;
          -  Myocardial infarction from coronary artery disease within 3 months of study enrollment&#xD;
&#xD;
          -  Implantable pacemaker or implantable cardioverter defibrillator&#xD;
&#xD;
          -  NYHA Class III or greater congestive heart failure&#xD;
&#xD;
          -  Other clinically-significant cardiac disorders&#xD;
&#xD;
          -  Family history of long QT syndrome.&#xD;
&#xD;
          -  Concomitant or expected treatment with strong inhibitors of cytochrome p450 CYP2D6,&#xD;
             specifically including Bupropion; Fluoxetine; or Paroxetine (must be discontinued at&#xD;
             least 2 weeks or 5-half lives prior to the initiation of desipramine, whichever is&#xD;
             shortest, except fluoxetine which requires at least a 5-week washout period).&#xD;
&#xD;
          -  Use of medications known to increase risk of torsades de pointes, including&#xD;
             Amiodarone; Arsenic trioxide; Astemizole; Azithromycin; Bepridil; Chloroquine;&#xD;
             Chlorpromazine; Cisapride; Citalopram; Clarithromycin; Disopyramide; Dofetilide;&#xD;
             Domperidone; Droperidol; Erythromycin; Flecainide; Halofantrine; Haloperidol;&#xD;
             Ibutilide; Levomethadyl; Mesoridazine; Methadone; Moxifloxacin; Pentamidine; Pimozide;&#xD;
             Probucol; Procainamide; Quinidine; Sotalol; Sparfloxacin; Terfenadine; Thioridazine;&#xD;
             Vandetanib&#xD;
&#xD;
          -  Other anti-depressant or anti-psychotic medications including selective serotonin&#xD;
             re-uptake inhibitors (SSRIs); other tricyclic, monoamine oxidase inhibitors (MAOIs);&#xD;
             serotonin-norepinephrine reuptake inhibitors (SNRIs, typical or atypical&#xD;
             anti-psychotic)&#xD;
&#xD;
          -  Metoclopramide (Reglan) because of increased risk of extrapyrimidal symptoms and&#xD;
             neuroleptic malignant syndrome&#xD;
&#xD;
          -  Symptomatic orthostatic hypotension despite adequate volume resuscitation.&#xD;
&#xD;
          -  Medical history of narrow angle glaucoma&#xD;
&#xD;
          -  Bipolar disorder, ongoing or active within the last 5 years&#xD;
&#xD;
          -  Suicidal ideation, ongoing or active within the last 5 years&#xD;
&#xD;
          -  Suicide attempt, ongoing or active within the last 5 years&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Breastfeeding&#xD;
&#xD;
          -  Receiving any other investigational agents&#xD;
&#xD;
          -  Any other serious or unstable concomitant systemic disorder that in the opinion of the&#xD;
             investigator is incompatible with the clinical study&#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>Joel W Neal, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University Cancer Institute</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>October 29, 2012</study_first_submitted>
  <study_first_submitted_qc>October 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 1, 2012</study_first_posted>
  <results_first_submitted>January 12, 2017</results_first_submitted>
  <results_first_submitted_qc>March 2, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 17, 2017</results_first_posted>
  <last_update_submitted>March 2, 2017</last_update_submitted>
  <last_update_submitted_qc>March 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 17, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Joel Neal</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Small Cell Lung Carcinoma</mesh_term>
    <mesh_term>Neuroendocrine Tumors</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Desipramine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>10 participants total were to be enrolled at Stanford Medical Center between December 2012 - December 2013</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Desipramine HCl 25 mg</title>
          <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Cycle 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Cycle 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Desipramine HCl</title>
          <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</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>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histology</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Small Cell Carcinoma of Lung</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Large Cell Neuroendocrine Carcinoma of Lung</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Large Cell Neuroendocrine Carcinoma of Pancreas</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Overall Response Rate (ORR)</title>
        <description>Overall response rate (ORR) was assessed as the number of patients who achieve either a partial (PR) or complete response (CR) measured by CT scans and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria, divided by the total number of patients treated on the study. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.</description>
        <time_frame>6 weeks</time_frame>
        <population>All patients who were enrolled and started therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Desipramine HCl 25 mg</title>
            <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR)</title>
          <description>Overall response rate (ORR) was assessed as the number of patients who achieve either a partial (PR) or complete response (CR) measured by CT scans and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria, divided by the total number of patients treated on the study. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.</description>
          <population>All patients who were enrolled and started therapy.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Desipramine Maximum Dose</title>
        <description>Assessed as the median per patient maximum dose (MD) using intra-patient dose escalation, and reported as the highest dose of desipramine administered continuously for 1 week or greater.</description>
        <time_frame>Up to 6 weeks</time_frame>
        <population>All patients who were enrolled and started therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Desipramine HCl</title>
            <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
          </group>
        </group_list>
        <measure>
          <title>Desipramine Maximum Dose</title>
          <description>Assessed as the median per patient maximum dose (MD) using intra-patient dose escalation, and reported as the highest dose of desipramine administered continuously for 1 week or greater.</description>
          <population>All patients who were enrolled and started therapy.</population>
          <units>mg daily</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75" lower_limit="75" upper_limit="300"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Serum Desipramine Levels During Treatment</title>
        <description>Median serum desipramine levels during treatment is reported as the median of the maximum steady state serum concentration observed in all patients.&#xD;
Therapeutic concentration of desipramine is 100 to 300 ng/mL, and toxic concentration is &gt; 300 ng/mL.</description>
        <time_frame>Up to 6 weeks</time_frame>
        <population>All patients who were enrolled and started therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Desipramine HCl</title>
            <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Serum Desipramine Levels During Treatment</title>
          <description>Median serum desipramine levels during treatment is reported as the median of the maximum steady state serum concentration observed in all patients.&#xD;
Therapeutic concentration of desipramine is 100 to 300 ng/mL, and toxic concentration is &gt; 300 ng/mL.</description>
          <population>All patients who were enrolled and started therapy.</population>
          <units>ng/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="132" lower_limit="0" upper_limit="490"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS), Median</title>
        <description>Median PFS was defined as the time from randomization to disease progression (or death if the patient died before progression) calculated using the Kaplan-Meier method.</description>
        <time_frame>Up to 5 years from enrollment to radiographic progression or drug discontinuation</time_frame>
        <population>All patients who were enrolled and started therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Desipramine HCl</title>
            <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS), Median</title>
          <description>Median PFS was defined as the time from randomization to disease progression (or death if the patient died before progression) calculated using the Kaplan-Meier method.</description>
          <population>All patients who were enrolled and started therapy.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.2" lower_limit="0.2" upper_limit="3.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Overall Survival (OS)</title>
        <description>Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method.</description>
        <time_frame>From start of enrollment until death, no limit</time_frame>
        <population>All patients who were enrolled and started therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Desipramine HCl</title>
            <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival (OS)</title>
          <description>Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method.</description>
          <population>All patients who were enrolled and started therapy.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.7" lower_limit="1.3" upper_limit="5.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Cycle 1 (28 days)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Desipramine HCl 25 mg</title>
          <description>Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. By the end of the 6 weeks, patients will be taking 450 mg (maximum dosage) or a tolerable dose of desipramine without serious side effects.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" 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" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Rectal Obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <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="6" 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" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Palpitation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rectal Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gastrointestional disorders, other - Black stools</sub_title>
                <counts group_id="E1" events="1" 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" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>General disorders, Other - night sweats</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ALT increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>AST increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Amnesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hallucinations</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders, Other - polyuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders, - nocturia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" events="1" 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" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" 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>This study had to be terminated early because patients with small cell lung cancer were not able to tolerate clinically relevant doses of desipramine, and no clinical activity was observed in the first enrolled patients.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Joel Neal, MD, PhD; Assistant Professor of Medicine</name_or_title>
      <organization>Stanford University Medical Center</organization>
      <phone>650-725-3081</phone>
      <email>jwneal@stanford.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/NCT01719861
org study id: IRB-25491
secondary id: VAR0087
nct id: NCT01719861
lead sponsor: 
has dmc: Yes
Intrapatient dose escalation study of desipramine in subjects with small cell lung cancer
      (SCLC) and other high-grade neuroendocrine tumors.
Participants will start desipramine by mouth nightly (QHS) for 6 weeks, with weekly dose
      escalation. Starting dose will be 25 to 75 mg. The desipramine dose will be escalated until
      the maximum dose of 450 mg is reached or a maximum safe dose per subject is established.

      Dose level may be adjusted (decreased) based on cardiac or general adverse effects.
      desipramine level will be tapered if the subject experience disease progression, unless
      physician judges immediate suspension is in the subjects best interest.

      Assessments will be conducted every 28 days, and will include ECGs, physicians and blood
      samples.

      One partial and/or complete response will be sufficient to consider a larger clinical trial.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate (ORR)
time frame: 6 weeks
description: Overall response rate (ORR) was assessed as the number of patients who achieve either a partial (PR) or complete response (CR) measured by CT scans and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria, divided by the total number of patients treated on the study. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.
measure: Desipramine Maximum Dose
time frame: Up to 6 weeks
description: Assessed as the median per patient maximum dose (MD) using intra-patient dose escalation, and reported as the highest dose of desipramine administered continuously for 1 week or greater.
measure: Median Serum Desipramine Levels During Treatment
time frame: Up to 6 weeks
description: Median serum desipramine levels during treatment is reported as the median of the maximum steady state serum concentration observed in all patients.
Therapeutic concentration of desipramine is 100 to 300 ng/mL, and toxic concentration is > 300 ng/mL.
measure: Progression-free Survival (PFS), Median
time frame: Up to 5 years from enrollment to radiographic progression or drug discontinuation
description: Median PFS was defined as the time from randomization to disease progression (or death if the patient died before progression) calculated using the Kaplan-Meier method.
measure: Median Overall Survival (OS)
time frame: From start of enrollment until death, no limit
description: Median overall survival was defined as time from enrollment to death from any cause calculated using the Kaplan-Meier method.
arm group label: Desipramine HCl
arm group type: Experimental
description: Desipramine is a tricyclic antidepressant (TCA).
intervention type: Drug
intervention name: Desipramine HCL
description: Desipramine is a tricyclic antidepressant (TCA). All patients will start off with a 25 mg dose by mouth nightly (QHS), increasing weekly for 6 weeks. The target dose level at 6 weeks is 450 mg (maximum dosage) or the maximum tolerated dose (MTD) for each subject.
arm group label: Desipramine HCl
other name: Norpramin
other name: Pertofrane
other name: Desmethylimipramine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joel W Neal, MD, PhD
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Stanford University
investigator full name: Joel Neal
investigator title: Assistant Professor
mesh term: Lung Neoplasms
mesh term: Small Cell Lung Carcinoma
mesh term: Neuroendocrine Tumors
mesh term: Desipramine
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study had to be terminated early because patients with small cell lung cancer were not able to tolerate clinically relevant doses of desipramine, and no clinical activity was observed in the first enrolled patients.
point of contact: 