<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/NCT02973399</url>
  </required_header>
  <id_info>
    <org_study_id>SNX-5422-CLN1-012</org_study_id>
    <nct_id>NCT02973399</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL</brief_title>
  <official_title>A Phase 1, Open-label Study of SNX-5422 Added to Ibrutinib in Chronic Lymphocytic Leukemia Subjects With Residual Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Esanex Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Esanex Inc.</source>
  <oversight_info>
    <has_dmc>No</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>
      SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of&#xD;
      the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome&#xD;
      ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the&#xD;
      addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in&#xD;
      subjects who have residual disease, but have not progressed on ibrutinib after 18 months of&#xD;
      monotherapy, and/or prevents or delays disease progression of subjects with CLL.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not&#xD;
      considered curable outside of allogeneic stem cell transplantation. Significant advances have&#xD;
      been made in the therapy, notably with the introduction of the Bruton's tyrosine kinase (BTK)&#xD;
      inhibitor ibrutinib.&#xD;
&#xD;
      While response to ibrutinib has been high with therapy well-tolerated overall, some patients&#xD;
      have relapsed while others have been taken off therapy for toxicity or other reasons. In&#xD;
      addition, although remissions are durable in many patients, very few patients achieve a&#xD;
      complete response (CR), and minimal residual disease (MRD) negativity on single agent&#xD;
      ibrutinib has not been reported. Since it is known that for chemoimmunotherapy as well as&#xD;
      targeted therapies such as venetoclax that attainment of a CR is associated with longer&#xD;
      progression free survival (PFS), it is likely that deepening responses associated with&#xD;
      ibrutinib will result in more durable remissions.&#xD;
&#xD;
      Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in&#xD;
      BTK, the other is through a variety of mutations in the immediate downstream target of BTK,&#xD;
      PLCγ2. SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule&#xD;
      inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may&#xD;
      overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate&#xD;
      whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical&#xD;
      response in subjects who have residual disease, but have not progressed on ibrutinib after 18&#xD;
      months of monotherapy.&#xD;
&#xD;
      Subjects will receive SNX-5422 (56 mg/m2) in the morning once every other day for 21 days (11&#xD;
      doses), followed by a 7-day drug-free period. Subjects will continue to receive daily oral&#xD;
      ibrutinib at their established dose level in the afternoon&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Low recruitment&#xD;
  </why_stopped>
  <start_date type="Actual">February 7, 2017</start_date>
  <completion_date type="Actual">February 4, 2019</completion_date>
  <primary_completion_date type="Actual">December 4, 2018</primary_completion_date>
  <phase>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>Efficacy of the combination of SNX-5422 and ibrutinib</measure>
    <time_frame>6 months</time_frame>
    <description>Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of subjects reporting adverse events</measure>
    <time_frame>Day 28 of each 4 week cycle from randomization up to 52 weeks</time_frame>
    <description>Frequency and severity of adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete response at 12 months</measure>
    <time_frame>12 months</time_frame>
    <description>Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improved Clinical Status</measure>
    <time_frame>6 months</time_frame>
    <description>Proportion of subjects obtaining improvement in clinical status (i.e., Stable Disease becoming Partial Response) at the end of 6 SNX-5422 treatment cycles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival of patients receiving ibrutinib plus SNX-5422</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Elapsed time for each subject from randomization to continued survival up to 52 weeks</description>
  </secondary_outcome>
  <other_outcome>
    <measure>BTK Mutation Level</measure>
    <time_frame>6 and 12 months</time_frame>
    <description>Change from baseline in percent of CLL cells with Bruton's Tyrosine Kinase mutations at the end of 6 and 12 treatment cycles</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Cancer</condition>
  <arm_group>
    <arm_group_label>SNX-5422 plus ibrutinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Open-label administration of SNX-5422 capsules dosed in the morning once every other day for 21 days (11 doses) followed by a 7 day drug free period and daily with the established ibrutinib dose for 28 days of a 28-days cycle. Subjects will repeat the 28-day schedule for 2 cycles after a CR or until the cancer progresses or the subject is unable to tolerate the therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SNX-5422 plus ibrutinib</intervention_name>
    <description>SNX-5422 capsule(s) dosed every other day for 21 days out of a 28-day treatment cycle to a total dose of 56 mg/m2 SNX-5422. Subjects will self-administer daily oral ibrutinib in the afternoon at least 8 hours apart from SNX-5422 for 28 days of each cycle.</description>
    <arm_group_label>SNX-5422 plus ibrutinib</arm_group_label>
    <other_name>Imbruvica</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males or non-pregnant, non-breastfeeding females 18 years-of-age or older&#xD;
&#xD;
          -  A diagnosis of CLL as defined by IWCLL 2008 criteria and currently on treatment with&#xD;
             ibrutinib for at least 18 months with residual disease and without evidence of disease&#xD;
             progression.&#xD;
&#xD;
          -  No more than 4 prior lines of anti leukemia therapy (not including ibrutinib)&#xD;
&#xD;
          -  Life expectancy of at least 9 months&#xD;
&#xD;
          -  Karnofsky performance score 70&#xD;
&#xD;
          -  Adequate baseline laboratory assessments&#xD;
&#xD;
          -  Signed informed consent form&#xD;
&#xD;
          -  Recovered from toxicities of previous anticancer therapy to CTCAE Grade ≤ 1&#xD;
&#xD;
          -  Subjects with reproductive capability must agree to practice adequate contraception&#xD;
             methods.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects experiencing toxicity with ibrutinib&#xD;
&#xD;
          -  Prior treatment with any Hsp90 inhibitor.&#xD;
&#xD;
          -  Major surgery or significant traumatic injury within 4 weeks of starting study&#xD;
             treatment.&#xD;
&#xD;
          -  Conventional chemotherapy or radiation within 4 weeks.&#xD;
&#xD;
          -  The need for treatment with medications with clinically-relevant metabolism by the&#xD;
             cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of&#xD;
             SNX-5422&#xD;
&#xD;
          -  Screening ECG QTc interval 470 msec for females, 450 msec for males.&#xD;
&#xD;
          -  At increased risk for developing prolonged QT interval unless corrected to within&#xD;
             normal limits prior to first dose of SNX-5422&#xD;
&#xD;
          -  Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate&#xD;
             medical management.&#xD;
&#xD;
          -  Gastrointestinal diseases or conditions that could affect drug absorption or could&#xD;
             alter the assessment of safety&#xD;
&#xD;
          -  History of documented adrenal dysfunction not due to malignancy.&#xD;
&#xD;
          -  History of chronic liver disease.&#xD;
&#xD;
          -  Active hepatitis A or B.&#xD;
&#xD;
          -  Current alcohol dependence or drug abuse.&#xD;
&#xD;
          -  Use of an investigational treatment (except for ibrutinib) from 30 days prior to the&#xD;
             first dose&#xD;
&#xD;
          -  Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected&#xD;
             by ophthalmological examination that are considered clinically important by examiner.&#xD;
&#xD;
          -  Psychological or social reasons that would hinder or prevent compliance with the&#xD;
             requirements of the protocol or compromise the informed consent process.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Weill Cornell Medical College</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wexner Medical Center, Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>November 22, 2016</study_first_submitted>
  <study_first_submitted_qc>November 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 25, 2016</study_first_posted>
  <last_update_submitted>February 21, 2019</last_update_submitted>
  <last_update_submitted_qc>February 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CLL</keyword>
  <keyword>Leukemia, Chronic Lymphocytic</keyword>
  <keyword>Hsp90</keyword>
  <keyword>Ibrutinib</keyword>
  <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/NCT02973399
org study id: SNX-5422-CLN1-012
nct id: NCT02973399
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of
      the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome
      ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the
      addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in
      subjects who have residual disease, but have not progressed on ibrutinib after 18 months of
      monotherapy, and/or prevents or delays disease progression of subjects with CLL.
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not
      considered curable outside of allogeneic stem cell transplantation. Significant advances have
      been made in the therapy, notably with the introduction of the Bruton's tyrosine kinase (BTK)
      inhibitor ibrutinib.

      While response to ibrutinib has been high with therapy well-tolerated overall, some patients
      have relapsed while others have been taken off therapy for toxicity or other reasons. In
      addition, although remissions are durable in many patients, very few patients achieve a
      complete response (CR), and minimal residual disease (MRD) negativity on single agent
      ibrutinib has not been reported. Since it is known that for chemoimmunotherapy as well as
      targeted therapies such as venetoclax that attainment of a CR is associated with longer
      progression free survival (PFS), it is likely that deepening responses associated with
      ibrutinib will result in more durable remissions.

      Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in
      BTK, the other is through a variety of mutations in the immediate downstream target of BTK,
      PLCγ2. SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule
      inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may
      overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate
      whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical
      response in subjects who have residual disease, but have not progressed on ibrutinib after 18
      months of monotherapy.

      Subjects will receive SNX-5422 (56 mg/m2) in the morning once every other day for 21 days (11
      doses), followed by a 7-day drug-free period. Subjects will continue to receive daily oral
      ibrutinib at their established dose level in the afternoon
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy of the combination of SNX-5422 and ibrutinib
time frame: 6 months
description: Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles
measure: Number of subjects reporting adverse events
time frame: Day 28 of each 4 week cycle from randomization up to 52 weeks
description: Frequency and severity of adverse events
measure: Complete response at 12 months
time frame: 12 months
description: Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles
measure: Improved Clinical Status
time frame: 6 months
description: Proportion of subjects obtaining improvement in clinical status (i.e., Stable Disease becoming Partial Response) at the end of 6 SNX-5422 treatment cycles
measure: Progression free survival of patients receiving ibrutinib plus SNX-5422
time frame: Up to 52 weeks
description: Elapsed time for each subject from randomization to continued survival up to 52 weeks
measure: BTK Mutation Level
time frame: 6 and 12 months
description: Change from baseline in percent of CLL cells with Bruton's Tyrosine Kinase mutations at the end of 6 and 12 treatment cycles
arm group label: SNX-5422 plus ibrutinib
arm group type: Experimental
description: Open-label administration of SNX-5422 capsules dosed in the morning once every other day for 21 days (11 doses) followed by a 7 day drug free period and daily with the established ibrutinib dose for 28 days of a 28-days cycle. Subjects will repeat the 28-day schedule for 2 cycles after a CR or until the cancer progresses or the subject is unable to tolerate the therapy
intervention type: Drug
intervention name: SNX-5422 plus ibrutinib
description: SNX-5422 capsule(s) dosed every other day for 21 days out of a 28-day treatment cycle to a total dose of 56 mg/m2 SNX-5422. Subjects will self-administer daily oral ibrutinib in the afternoon at least 8 hours apart from SNX-5422 for 28 days of each cycle.
arm group label: SNX-5422 plus ibrutinib
other name: Imbruvica
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: United States
responsible party type: Sponsor
sharing ipd: No