<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/NCT03761069</url>
  </required_header>
  <id_info>
    <org_study_id>PTC299-HEM-001-LEU</org_study_id>
    <nct_id>NCT03761069</nct_id>
  </id_info>
  <brief_title>Study of PTC299 (Emvododstat) in Relapsed/Refractory Acute Leukemias</brief_title>
  <official_title>Phase 1B Study of PTC299 in Relapsed/Refractory Acute Leukemias</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>PTC Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>PTC Therapeutics</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 is an open-label, non-randomized, Phase 1b study to evaluate the safety,&#xD;
      pharmacokinetics (PK) profiles, and preliminary evidence of antitumor activity of PTC299 and&#xD;
      the metabolite, O-desmethyl PTC299, in participants with relapsed/refractory acute myeloid&#xD;
      leukemia (AML) who have exhausted standard available therapies known to provide clinical&#xD;
      benefit. The study is designed as a series of cohort-based dose escalations. For each cohort,&#xD;
      a minimum of 3 evaluable participants with PK and safety data will be assessed. Additional&#xD;
      participants will be recruited if additional PK data are needed to assess mean exposure based&#xD;
      on the observed variability.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sponsor terminated the study.&#xD;
  </why_stopped>
  <start_date type="Actual">October 29, 2018</start_date>
  <completion_date type="Actual">December 28, 2021</completion_date>
  <primary_completion_date type="Actual">December 28, 2021</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>Number of Participants Who Discontinued Study Drug Due to Adverse Event (AE)</measure>
    <time_frame>From Screening to 50 days post treatment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Maximum Plasma Concentration (Tmax) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentration (Cmax) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Concentration-Time Curve (AUC) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life (t1/2) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Estimate t1/2 of of both PTC299 and O-desmethyl PTC299 During 14-Day Washout Period</measure>
    <time_frame>Day 29 through Day 42</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Clearance (CL/F) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Volume of Distribution (Vz/F) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation Ratio (R) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food</measure>
    <time_frame>Days 1, 15, 28, 57, 71 and 99</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Achieving Response Rate/Overall Response Rate Utilizing International Working Group (IWG) Response Criteria for AML</measure>
    <time_frame>Up to 6 Months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Leukemia, Myeloid, Acute</condition>
  <condition>AML</condition>
  <arm_group>
    <arm_group_label>PTC299</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PTC299 will be administered orally once daily (QD) for each 28-day cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PTC299</intervention_name>
    <description>PTC299 will be administered per the treatment arm description</description>
    <arm_group_label>PTC299</arm_group_label>
    <other_name>Emvododstat</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participant must have relapsed/refractory AML and exhausted standard available&#xD;
             therapies known to provide clinical benefit.&#xD;
&#xD;
          -  Subjects must be greater than or equal to 18 years of age.&#xD;
&#xD;
          -  Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status less&#xD;
             than or equal to (≤) 2&#xD;
&#xD;
          -  Women of childbearing potential must be willing to practice a highly-effective method&#xD;
             of birth control for up to 50 days after the last dose of study drug.&#xD;
&#xD;
          -  A man who is sexually active with a woman of childbearing potential and has not had a&#xD;
             vasectomy must agree to use a barrier method of birth control during the study and for&#xD;
             up to 50 days after the last dose of study drug.&#xD;
&#xD;
          -  Subjects must be willing to participate to the study, have the ability to understand&#xD;
             and adhere to study visit schedule and other protocol procedures, and be able and&#xD;
             willing to sign a written informed consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Medical history:&#xD;
&#xD;
          -  Women who are or plan to become pregnant, or who are currently breastfeeding.&#xD;
&#xD;
          -  Persistence of any clinically relevant (Common Terminology Criteria for Adverse Events&#xD;
             [CTCAE] Grade 2 or above) toxicities from previous therapy.&#xD;
&#xD;
          -  Active alcohol or drug abuse.&#xD;
&#xD;
          -  Previous drug-induced liver injury.&#xD;
&#xD;
        Cardiac assessments:&#xD;
&#xD;
          -  Uncontrolled congestive heart failure, unstable angina pectoris.&#xD;
&#xD;
          -  History or current evidence of a myocardial infarction during the last 6 months.&#xD;
&#xD;
          -  QTc prolongation greater than (&gt;) 500 milliseconds (msec) (Fridericia formula).&#xD;
&#xD;
          -  Congenitally long QT syndrome or has received any marketed or experimental compound in&#xD;
             the last 4 weeks or 5 half-lives (whichever is shorter) prior to entering the study&#xD;
             with possible or known effects of QT prolongation. (If equivalent medication is not&#xD;
             available, QTc will be closely monitored.)&#xD;
&#xD;
        Laboratory assessments:&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than or&#xD;
             equal to (≥) 1 * upper limit of normal (ULN).&#xD;
&#xD;
          -  Serum bilirubin ≥ 1 * ULN (except those known to have Gilbert's syndrome).&#xD;
&#xD;
          -  Creatinine clearance ≤45 milliliters per minute (mL/min) (estimated by Cockcroft-Gault&#xD;
             or by 24-hour urine collection).&#xD;
&#xD;
          -  Any laboratory abnormality, which in the opinion of the investigator, places the&#xD;
             participant at an unacceptably high risk for toxicities.&#xD;
&#xD;
        Gastrointestinal (GI) assessments:&#xD;
&#xD;
          -  Liver malignancy (including metastases) or chronic liver disease.&#xD;
&#xD;
          -  History of Gastrointestinal surgery or procedures or conditions that might interfere&#xD;
             with the absorption or swallowing of the study drug.&#xD;
&#xD;
        Immunologic:&#xD;
&#xD;
          -  Known hypersensitivity to study drug or its excipients.&#xD;
&#xD;
        Miscellaneous:&#xD;
&#xD;
          -  Any sign of active uncontrolled infections; any severe chronic disease potentially&#xD;
             interfering with the protocol, including human immunodeficiency virus (HIV) infection,&#xD;
             or active hepatitis B or C or those with a positive screen for hepatitis A&#xD;
             Immunoglobulin M (IgM).&#xD;
&#xD;
          -  Any other malignancies within the past 2 years other than basal cell skin cancer or&#xD;
             carcinoma in situ of the cervix.&#xD;
&#xD;
          -  Participant concomitantly receiving any other investigational agents.&#xD;
&#xD;
          -  Systemic chemotherapy within 2 weeks or investigational therapy within 5 half-lives&#xD;
             prior to first dose of study drug, unless there is evidence of rapidly progressive&#xD;
             disease (in which case the shorter washout of 2 weeks will be followed). For&#xD;
             monoclonal antibodies, the washout from prior therapy will be 4 weeks, unless there is&#xD;
             evidence of rapidly progressive disease, in which case, the shorter washout period of&#xD;
             2 weeks will be followed. Persistent chronic clinically significant toxicities from&#xD;
             prior chemotherapy must not be &gt;Grade 1. Use of hydroxyurea (Hydrea) is permitted up&#xD;
             to 24 hours prior to start of study drug for control of proliferative disease. Hydrea&#xD;
             treatment may be reinstated during study for control of proliferative disease, as&#xD;
             needed, at the discretion of investigator.&#xD;
&#xD;
          -  Participants with AML that has advanced with central nervous system (CNS) involvement.&#xD;
&#xD;
          -  Participant is pregnant or breastfeeding or expecting to conceive or father children&#xD;
             within the projected duration of the study.&#xD;
&#xD;
          -  Participants receiving CYP2B6 substrates such as bupropion and methadone.&#xD;
&#xD;
          -  Participants receiving strong CYP3A4 inducers such as carbamazepine, enzalutamide,&#xD;
             mitotane, phenytoin, rifampin, and St. John's wort (hypericin) or drugs that are&#xD;
             exclusively substrates of CYP3A4.&#xD;
&#xD;
          -  Participant is receiving moderate or strong CYP3A4 inhibitors. (Note: This exclusion&#xD;
             criterion is not applicable to subjects participating in sub-study where only subjects&#xD;
             who are currently on/require antifungals [prophylaxis/treatment] will be enrolled)&#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>Rocky Mountain Cancer Center</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80012</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry Ford Health System</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers, Cancer Institute of NJ</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester MC</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke Cancer Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gabrail Cancer Center</name>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <zip>44718</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oncology Hematology Care, Inc.</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45236</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic Foundation</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rhode Island, Miriam Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SCRI Tennessee Oncology</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology, P.A.</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology, P.A.</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <zip>76104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Oncology, P.A. - San Antonio Medical Center</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78240</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Swedish Cancer Institute</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>91804</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>November 29, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>January 18, 2022</last_update_submitted>
  <last_update_submitted_qc>January 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Leukemia, Myeloid</keyword>
  <keyword>Neoplasms by Histologic Type</keyword>
  <keyword>Neoplasms</keyword>
  <keyword>Dihydroorotate dehydrogenase (DHODH) inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_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/NCT03761069
org study id: PTC299-HEM-001-LEU
nct id: NCT03761069
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is an open-label, non-randomized, Phase 1b study to evaluate the safety,
      pharmacokinetics (PK) profiles, and preliminary evidence of antitumor activity of PTC299 and
      the metabolite, O-desmethyl PTC299, in participants with relapsed/refractory acute myeloid
      leukemia (AML) who have exhausted standard available therapies known to provide clinical
      benefit. The study is designed as a series of cohort-based dose escalations. For each cohort,
      a minimum of 3 evaluable participants with PK and safety data will be assessed. Additional
      participants will be recruited if additional PK data are needed to assess mean exposure based
      on the observed variability.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants Who Discontinued Study Drug Due to Adverse Event (AE)
time frame: From Screening to 50 days post treatment
measure: Time to Maximum Plasma Concentration (Tmax) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Maximum Plasma Concentration (Cmax) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Area Under the Concentration-Time Curve (AUC) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Half-life (t1/2) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Estimate t1/2 of of both PTC299 and O-desmethyl PTC299 During 14-Day Washout Period
time frame: Day 29 through Day 42
measure: Apparent Clearance (CL/F) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Apparent Volume of Distribution (Vz/F) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Accumulation Ratio (R) of both PTC299 and O-desmethyl PTC299 when PTC299 is Given as Tablet with Food
time frame: Days 1, 15, 28, 57, 71 and 99
measure: Percentage of Participants Achieving Response Rate/Overall Response Rate Utilizing International Working Group (IWG) Response Criteria for AML
time frame: Up to 6 Months
arm group label: PTC299
arm group type: Experimental
description: PTC299 will be administered orally once daily (QD) for each 28-day cycle.
intervention type: Drug
intervention name: PTC299
description: PTC299 will be administered per the treatment arm description
arm group label: PTC299
other name: Emvododstat
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
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facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute