<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/NCT03008018</url>
  </required_header>
  <id_info>
    <org_study_id>KTP-003</org_study_id>
    <nct_id>NCT03008018</nct_id>
  </id_info>
  <brief_title>Safety,Tolerability and MTD KA2507 (HDAC6 Inhibitor) in Patients With Solid Tumours</brief_title>
  <acronym>HDAC6i</acronym>
  <official_title>An Open Label Ascending Dose Study Evaluating the Safety/Tolerability, Pharmacokinetic and Pharmacodynamic Effects of KA2507 in Patients With Solid Tumours</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karus Therapeutics Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Karus Therapeutics Limited</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>
      The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and&#xD;
      pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients&#xD;
      with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment&#xD;
      will be eligible to participate in this study.&#xD;
&#xD;
      Following completion of the multiple ascending dose study, the protocol may be amended to&#xD;
      include expansion cohorts in patients with melanoma and/or other solid tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and&#xD;
      pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients&#xD;
      with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment&#xD;
      will be eligible to participate in this study.&#xD;
&#xD;
      Following completion of the multiple ascending dose study, the protocol may be amended to&#xD;
      include expansion cohorts in patients with melanoma and/or other solid tumors.&#xD;
&#xD;
      This is a multiple ascending dosing (MAD) study of up to 6 treatment regimens cohorts based&#xD;
      on using a 3+3 design (up to 36 patients overall). The principal objective is to establish&#xD;
      the maximum tolerated dose, safety, tolerability and pharmacokinetic (PK) profile in blood&#xD;
      and urine of this HDAC6 inhibitor in patients with solid tumors and to explore effects on&#xD;
      pharmacodynamic markers of target engagement and response to treatment.&#xD;
&#xD;
      Daily/twice daily doses will be given as open label monotherapy. A review of safety and PK&#xD;
      data will be conducted once the last patient in each cohort reaches day 28 of treatment. The&#xD;
      review will confirm the dose to be used for the subsequent cohort. Dose escalation will be&#xD;
      continued until the MTD is reached. Upon completion of the dose escalation phase of the&#xD;
      study, dose expansion phases will be planned.&#xD;
&#xD;
      Patients responding to treatment may elect to remain on therapy until disease progression,&#xD;
      death or the investigator decides to stop treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 7, 2017</start_date>
  <completion_date type="Actual">June 10, 2020</completion_date>
  <primary_completion_date type="Actual">June 10, 2020</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>The occurrence of dose limiting toxicity</measure>
    <time_frame>28 days</time_frame>
    <description>1. Any event with possible or probable relationship to study drug occurring up to day 28 from the start of treatment as assessed using the National Cancers Institutes Common Terminology Criteria for Adverse events version 4.03 therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Concentration of KA2507 in plasma over time (hours) post dosing</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration of KA2507 in urine over time (hours) post dosing</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood concentration of histone acetylation during KA2507 treatment</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood concentration of tubulin during KA2507 treatment</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical outcomes using the RECIST 1.1 criteria</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical outcomes using Immuno-RECIST criteria</measure>
    <time_frame>24 weeks</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Concentration of PD-L1 expression in tumor tissue</measure>
    <time_frame>24 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Concentration of MHC-1 expression in tumor tissue</measure>
    <time_frame>24 weeks</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Solid Tumor, Adult</condition>
  <arm_group>
    <arm_group_label>KA2507 (HDAC6 inhibitor)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This is a single arm dose escalating study. Patients will be treated with open label KA2507 (HDAC6 inhibitor) capsules.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>KA2507</intervention_name>
    <description>KA2507, an orally-active new chemical entity, is a potent and selective inhibitor of the HDAC6 enzyme, with potential clinical utility in the treatment of melanoma and other solid tumors. KA2507 has been shown to display potent in vitro activity in a range of cancer cell lines, including melanoma cell lines. KA2507 exerts potent in vivo efficacy in a syngeneic model of B16 melanoma. Here, the combination of the agent's direct tumor growth inhibition and metastasis suppression, coupled with its immunotherapeutic activity - demonstrated by decreased expression of STAT-3 and PD-L1 and increased expression of acetylated tubulin, gp100 and MHC Class I in tumors - have been observed.</description>
    <arm_group_label>KA2507 (HDAC6 inhibitor)</arm_group_label>
    <other_name>HDAC6 Inhibitor</other_name>
    <other_name>HDAC6i</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥18 years at the screening visit.&#xD;
&#xD;
          2. Patients with histologically or cytologically documented, confirmed diagnosis of&#xD;
             advanced malignancy, whose disease failed to respond to or progressed after standard&#xD;
             therapy or they could not tolerate standard therapy.&#xD;
&#xD;
          3. Measurable or evaluable disease according to RECIST v1.1.&#xD;
&#xD;
          4. ECOG performance status of 0 or 1.&#xD;
&#xD;
          5. Predicted life expectancy ≥12 weeks.&#xD;
&#xD;
          6. For men and women of child-bearing potential, willing to use adequate contraception&#xD;
             (i.e., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire&#xD;
             duration of the study.&#xD;
&#xD;
        1. If female, must be either postmenopausal, sterilised or, if sexually active, effectively&#xD;
        practicing an acceptable method of contraception (either oral, parenteral, or implantable&#xD;
        hormonal contraceptives, intrauterine device or barrier and spermicide). Subjects must&#xD;
        agree to use adequate contraception during the study and for at least 12 weeks (or longer&#xD;
        as per local requirement) after the last dose of study treatment.&#xD;
&#xD;
        2. Male subjects agree to ensure that they or their female partner(s) use adequate&#xD;
        contraception during the study and for at least 12 weeks (or longer as per local&#xD;
        requirement) after the subject receives their last dose of study treatment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients are not able to provide written informed consent to study participation&#xD;
&#xD;
          2. Patients who have been treated with most recent radiotherapy, hormonal therapy,&#xD;
             immunotherapy, chemotherapy or investigational drugs within ≤21 days or 5 half-lives&#xD;
             (whichever is shorter) from enrolment (screening), and/or who have any unresolved NCI&#xD;
             Common Terminology Criteria of Adverse Events (CTCAE) v4.03 &gt; Grade 1&#xD;
             treatment-related side effect (with the exception of alopecia).&#xD;
&#xD;
          3. Patient has anemia due to HbS or HbC disease, alpha or beta thalassaemia&#xD;
&#xD;
          4. Patient has Glucose-6-phosphate deficiency&#xD;
&#xD;
          5. Patient has known or suspected history of cytochrome b5-MetHb-reductase pathway&#xD;
             deficiency&#xD;
&#xD;
          6. Persons of Navajo, Athabaska Alaskan or Siberian Yakutsk descent&#xD;
&#xD;
          7. Patient has untreated severe hypothyroidism&#xD;
&#xD;
          8. Patient has laboratory estimations indicating organ system dysfunction:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) &lt;1.5 X 109/L&#xD;
&#xD;
               2. Platelets &lt;100 X 109/L&#xD;
&#xD;
               3. Hemoglobin &lt;9g/dL&#xD;
&#xD;
               4. Total bilirubin &gt;1.5 mg/dL&#xD;
&#xD;
               5. ALT and AST &gt;3.0 times the ULN if no liver involvement or &gt;5 times the ULN with&#xD;
                  liver involvement.&#xD;
&#xD;
               6. Calculated creatinine clearance &lt;60mL/min estimated using the Cockcroft-Gault&#xD;
                  equation:&#xD;
&#xD;
                  • Cockcroft-Gault equation: creatinine clearance = (140 - age in years) x (wt in&#xD;
                  kg)) x 1.23) / (serum creatinine in micromol/l) [For women multiply the result of&#xD;
                  calculation by 0.85].&#xD;
&#xD;
          9. Major surgery (excluding placement of vascular access) ≤21 days from beginning of the&#xD;
             study drug or minor surgical procedures ≤7 days. No waiting is required following&#xD;
             implantable port and catheter placement.&#xD;
&#xD;
         10. Any of the following cardiac criteria:&#xD;
&#xD;
               1. Congestive heart failure (CHF), grade III or IV per New York Heart Association&#xD;
                  (NYHA) classification&#xD;
&#xD;
               2. Symptomatic cardiomyopathy&#xD;
&#xD;
               3. &gt; Class II Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy&#xD;
&#xD;
               4. Unstable angina or new-onset angina&#xD;
&#xD;
               5. QTcF interval &gt;470 ms on screening ECG.&#xD;
&#xD;
        9. Severe or uncontrolled systemic diseases including uncontrolled hypertension, active&#xD;
        bleeding diatheses 10. Any evidence of active infection including active Hepatitis B,&#xD;
        Hepatitis C or human immunodeficiency virus 11. The patient has concurrent severe and/or&#xD;
        uncontrolled medical disease that could compromise participation in the study (i.e.,&#xD;
        uncontrolled diabetes, severe infection requiring active treatment, severe malnutrition,&#xD;
        chronic severe liver or renal disease, uncontrolled hypertension, active bleeding&#xD;
        diatheses).&#xD;
&#xD;
        12. Active infection requiring IV antibiotics within two weeks prior to treatment, or&#xD;
        evidence of TB infection.&#xD;
&#xD;
        13. Hepatitis B, Hepatitis C or human immunodeficiency virus 14. Previously untreated brain&#xD;
        metastases. Patients who have received radiation or surgery for brain metastases are&#xD;
        eligible if therapy was completed at least 3 weeks previously and there is no evidence of&#xD;
        central nervous system disease progression, mild neurologic symptoms, and no requirement&#xD;
        for chronic corticosteroid therapy.&#xD;
&#xD;
        15. Lactating, breastfeeding, or positive pregnancy test for female patients of&#xD;
        child-bearing potential.&#xD;
&#xD;
        16. The patient is unable to swallow capsules and/or has a surgical or anatomical condition&#xD;
        that precludes swallowing and absorbing oral medication on an ongoing basis (for oral&#xD;
        therapy only).&#xD;
&#xD;
        17. Patients with prior stem cell transplantation or solid organ transplantation.&#xD;
&#xD;
        18. History of other malignancies (except for adequately treated basal or squamous cell&#xD;
        carcinoma or carcinoma in situ) within the last 3 years.&#xD;
&#xD;
        17. Any other condition that would, in the investigator's judgment, contraindicate the&#xD;
        patient's participation in the clinical study due to safety concerns or compliance with&#xD;
        clinical study procedures.&#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>M D Anderson</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>December 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <last_update_submitted>August 18, 2020</last_update_submitted>
  <last_update_submitted_qc>August 18, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 19, 2020</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>Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03008018
org study id: KTP-003
nct id: NCT03008018
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and
      pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients
      with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment
      will be eligible to participate in this study.

      Following completion of the multiple ascending dose study, the protocol may be amended to
      include expansion cohorts in patients with melanoma and/or other solid tumors.
The aim of the study is to evaluate the safety/tolerability, pharmacokinetic, and
      pharmaco-dynamic effects of KA2507 and establish the maximum tolerated dose (MTD). Patients
      with PD-L1 expressing solid tumors which have relapsed or are refractory to prior treatment
      will be eligible to participate in this study.

      Following completion of the multiple ascending dose study, the protocol may be amended to
      include expansion cohorts in patients with melanoma and/or other solid tumors.

      This is a multiple ascending dosing (MAD) study of up to 6 treatment regimens cohorts based
      on using a 3+3 design (up to 36 patients overall). The principal objective is to establish
      the maximum tolerated dose, safety, tolerability and pharmacokinetic (PK) profile in blood
      and urine of this HDAC6 inhibitor in patients with solid tumors and to explore effects on
      pharmacodynamic markers of target engagement and response to treatment.

      Daily/twice daily doses will be given as open label monotherapy. A review of safety and PK
      data will be conducted once the last patient in each cohort reaches day 28 of treatment. The
      review will confirm the dose to be used for the subsequent cohort. Dose escalation will be
      continued until the MTD is reached. Upon completion of the dose escalation phase of the
      study, dose expansion phases will be planned.

      Patients responding to treatment may elect to remain on therapy until disease progression,
      death or the investigator decides to stop treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The occurrence of dose limiting toxicity
time frame: 28 days
description: 1. Any event with possible or probable relationship to study drug occurring up to day 28 from the start of treatment as assessed using the National Cancers Institutes Common Terminology Criteria for Adverse events version 4.03 therapy.
measure: Concentration of KA2507 in plasma over time (hours) post dosing
time frame: 24 weeks
measure: Concentration of KA2507 in urine over time (hours) post dosing
time frame: 24 weeks
measure: Blood concentration of histone acetylation during KA2507 treatment
time frame: 24 weeks
measure: Blood concentration of tubulin during KA2507 treatment
time frame: 24 weeks
measure: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
time frame: 24 weeks
measure: Clinical outcomes using the RECIST 1.1 criteria
time frame: 24 weeks
measure: Clinical outcomes using Immuno-RECIST criteria
time frame: 24 weeks
measure: Concentration of PD-L1 expression in tumor tissue
time frame: 24 weeks
measure: Concentration of MHC-1 expression in tumor tissue
time frame: 24 weeks
arm group label: KA2507 (HDAC6 inhibitor)
arm group type: Other
description: This is a single arm dose escalating study. Patients will be treated with open label KA2507 (HDAC6 inhibitor) capsules.
intervention type: Drug
intervention name: KA2507
description: KA2507, an orally-active new chemical entity, is a potent and selective inhibitor of the HDAC6 enzyme, with potential clinical utility in the treatment of melanoma and other solid tumors. KA2507 has been shown to display potent in vitro activity in a range of cancer cell lines, including melanoma cell lines. KA2507 exerts potent in vivo efficacy in a syngeneic model of B16 melanoma. Here, the combination of the agent's direct tumor growth inhibition and metastasis suppression, coupled with its immunotherapeutic activity - demonstrated by decreased expression of STAT-3 and PD-L1 and increased expression of acetylated tubulin, gp100 and MHC Class I in tumors - have been observed.
arm group label: KA2507 (HDAC6 inhibitor)
other name: HDAC6 Inhibitor
other name: HDAC6i
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
sharing ipd: Undecided