<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/NCT03834584</url>
  </required_header>
  <id_info>
    <org_study_id>AG636-C-001</org_study_id>
    <nct_id>NCT03834584</nct_id>
  </id_info>
  <brief_title>A Study of AG-636 in the Treatment of Subjects With Advanced Lymphoma</brief_title>
  <official_title>A Phase 1 Study of AG-636 in the Treatment of Subjects With Advanced Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Agios Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Agios Pharmaceuticals, 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>
      This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical&#xD;
      activity of AG-636, an oral Dihydroorotate Dehydrogenase (DHODH) inhibitor, in subjects with&#xD;
      advanced lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this Phase 1, multicenter, open-label study is to determine the maximum&#xD;
      tolerated dose (MTD) of AG-636 and characterize its dose-limiting toxicities (DLTs) when&#xD;
      given by mouth to subjects with advanced lymphoma that is refractory to standard treatment.&#xD;
      During the dose escalation part of the study successive cohorts of subjects will be treated&#xD;
      with increasing doses of AG-636 in order to determine its maximum tolerated dose (MTD).&#xD;
      Subsequently, in the dose expansion part of the study, additional subjects will be treated at&#xD;
      the MTD in order to confirm that dose's safety, tolerability, PK and PD, and to provide an&#xD;
      opportunity to detect anti-lymphoma activity. The dose expansion part of the study will&#xD;
      support the selection of a dose for future clinical studies (a recommended Phase 2 dose&#xD;
      [RP2D]).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Terminated due to sponsor decision.&#xD;
  </why_stopped>
  <start_date type="Actual">May 24, 2019</start_date>
  <completion_date type="Actual">June 17, 2020</completion_date>
  <primary_completion_date type="Actual">June 17, 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 frequency of dose limiting toxicities (DLTs) associated with AG-636 administration during the first cycle (first 28 days) of treatment.</measure>
    <time_frame>Up to 28 days, on average</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characterize the Safety and Tolerability of AG-636 (number of treatment-related Adverse Events and Serious Adverse Events)</measure>
    <time_frame>Up to 24 weeks, on average</time_frame>
    <description>As determined by the number of treatment-related Adverse Events and Serious Adverse Events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Characterize the Pharmacodynamics of AG-636</measure>
    <time_frame>Up to 24 weeks, on average</time_frame>
    <description>Measured by changes from baseline in circulating upstream metabolites</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of AG-636 in plasma</measure>
    <time_frame>Up to 24 weeks, on average</time_frame>
    <description>Determined by the plasma concentration versus time profile of AG-636</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical activity of AG-636 in Lymphoma</measure>
    <time_frame>Up to 24 weeks, on average</time_frame>
    <description>Assessed by either the Lugano criteria for lymphoma or the 2011 International Society for Cutaneous Lymphomas (ISCL)/United States Cutaneous Lymphoma Consortium (USCLC)/ European Organization for Research and Treatment of Cancer (EORTC) criteria for mycosis fungoides (MF)/Sézary syndrome (SS)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Lymphoma</condition>
  <arm_group>
    <arm_group_label>AG-636</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AG-636 dosed orally.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AG-636</intervention_name>
    <description>AG-636 will be administered orally intermittently in 28-day cycles.</description>
    <arm_group_label>AG-636</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be ≥18 years of age.&#xD;
&#xD;
          2. Have a pathologically confirmed diagnosis of a non-Hodgkin or Hodgkin lymphoma that&#xD;
             has progressed in spite of prior treatment, and for whom additional effective&#xD;
             (curative or life-prolonging) standard therapy is not available. The lymphomas&#xD;
             included in this study must fall within one of the following 2017 World Health&#xD;
             Organization categories:&#xD;
&#xD;
               1. Mature B-cell neoplasms (excluding plasma cell neoplasms, heavy chain disease,&#xD;
                  and primary central nervous system [CNS] lymphoma)&#xD;
&#xD;
               2. Mature T- and NK-cell neoplasms&#xD;
&#xD;
               3. Hodgkin lymphomas&#xD;
&#xD;
               4. Immunodeficiency-associated lymphoproliferative disorders&#xD;
&#xD;
          3. In the case of subjects who have lymphoma for which high-dose chemotherapy and&#xD;
             autologous stem cell transplantation (HD-ASCT) is considered a standard curative&#xD;
             therapy, eligibility for this study requires that the subject's disease has relapsed&#xD;
             after HD-ASCT, that the subject is not eligible for HD-ASCT, or that the subject has&#xD;
             refused HD-ASCT.&#xD;
&#xD;
          4. Have disease that can be clinically evaluated for improvement or progression. In the&#xD;
             dose expansion phase of the study, subjects must have disease that is measurable (as&#xD;
             defined by either the Lugano criteria for lymphoma or the 2011 ISCL/USCLC/EORTC&#xD;
             criteria for MF/SS).&#xD;
&#xD;
          5. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.&#xD;
&#xD;
          6. Have an absolute neutrophil count (ANC) ≥1,000/uL.&#xD;
&#xD;
          7. Have a platelet count ≥75,000/uL.&#xD;
&#xD;
          8. Have a serum total bilirubin level ≤1.5×ULN (upper limit of normal) in the absence of&#xD;
             Gilbert syndrome. Subjects with Gilbert syndrome must have a serum total bilirubin&#xD;
             level ≤1.5× their baseline value.&#xD;
&#xD;
          9. Have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels&#xD;
             ≤3.0×ULN, unless due to underlying hematologic malignancy. If ALT/AST elevations are&#xD;
             determined to be due to involvement by the underlying hematologic malignancy, subjects&#xD;
             must have ALT/AST levels &lt;5.0× the ULN.(Note: There are no specific requirements for&#xD;
             alkaline phosphatase [ALP].)&#xD;
&#xD;
         10. Have a creatinine clearance (CrCl) ≥ 30 mL/min (either measured or estimated by the&#xD;
             Cockcroft-Gault formula). (Cockcroft-Gault formula for estimated creatinine clearance&#xD;
             [eCrCl]: eCrCl = [140 - Age] × Weight [kg] × [0.85 if Female] / [72 × serum creatinine&#xD;
             (mg/dL)]).&#xD;
&#xD;
         11. Be fully recovered from major surgery and from the acute toxic effects of prior&#xD;
             chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy, eg,&#xD;
             alopecia, Grade ≤2 peripheral neuropathy, are allowed.&#xD;
&#xD;
         12. If female with reproductive potential, must have a negative serum pregnancy test prior&#xD;
             to the start of study therapy. Females of reproductive potential, as well as fertile&#xD;
             men and their female partners of reproductive potential, must agree to use 2 effective&#xD;
             forms of contraception.&#xD;
&#xD;
         13. Able to understand and have provided written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Have a primary central nervous system (CNS) lymphoma.&#xD;
&#xD;
          2. Have lymphomatous involvement of the CNS that is symptomatic or requires therapy.&#xD;
             However, subjects who have completed treatment for lymphoma involving the CNS and have&#xD;
             no further evidence of disease in the CNS may be enrolled in this study.&#xD;
&#xD;
          3. Have lymphoma that requires immediate cytoreductive therapy.&#xD;
&#xD;
          4. Have low-grade lymphoma that does not meet conventional criteria for requiring&#xD;
             treatment.&#xD;
&#xD;
          5. Have impairment of gastrointestinal (GI) function or GI disease that may significantly&#xD;
             alter the absorption of AG-636, including any unresolved nausea, vomiting, or diarrhea&#xD;
             that is National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events&#xD;
             (CTCAE) Grade &gt;1.&#xD;
&#xD;
          6. Are unable to abstain from food or liquids other than water for 2 hours before and 2&#xD;
             hours after each dose of AG-636.&#xD;
&#xD;
          7. Have an active infection with human immunodeficiency virus (HIV), hepatitis B, or&#xD;
             hepatitis C.&#xD;
&#xD;
          8. Have an active infection (bacterial, viral, or fungal) that cannot be controlled with&#xD;
             treatment.&#xD;
&#xD;
          9. Have had significant active cardiac disease within 6 months prior to the start of&#xD;
             study treatment, including any of the following:&#xD;
&#xD;
               1. New York Heart Association (NYHA) class III or IV congestive heart failure.&#xD;
&#xD;
               2. Acute myocardial infarction or angina pectoris.&#xD;
&#xD;
               3. Stroke.&#xD;
&#xD;
               4. Uncontrolled cardiac arrhythmia (subjects with rate-controlled atrial&#xD;
                  fibrillation are not excluded).&#xD;
&#xD;
         10. Have a heart rate-corrected QT interval using Fridericia's method (QTcF) &gt;470 msec.&#xD;
             Patients with bundle branch block and a QTcF &gt;470 msec should be discussed with the&#xD;
             Medical Monitor for potential inclusion.&#xD;
&#xD;
         11. Have any other concurrent severe and/or uncontrolled concomitant medical condition&#xD;
             that could compromise participation in the study (eg, clinically significant pulmonary&#xD;
             disease, clinically significant neurologic disorder).&#xD;
&#xD;
         12. Have received any systemic anticancer treatment or radiotherapy less than 2 weeks&#xD;
             before the first dose of AG-636.&#xD;
&#xD;
         13. Have received radioimmunotherapy less than 6 weeks before the first dose of AG-636.&#xD;
&#xD;
         14. Have received treatment with an investigational small molecule &lt;2 weeks before the&#xD;
             first dose of AG-636.&#xD;
&#xD;
         15. Are taking medications that are sensitive substrates of CYP2C8, and that cannot be&#xD;
             discontinued prior to starting treatment with AG-636.&#xD;
&#xD;
         16. Are taking medications that are sensitive substrates of either P-glycoprotein (P-gp)&#xD;
             or breast cancer resistance protein (BCRP), and that cannot be discontinued prior to&#xD;
             starting treatment with AG-636.&#xD;
&#xD;
         17. Are pregnant or breastfeeding.&#xD;
&#xD;
         18. Have any other medical or psychological condition deemed by the Investigator to be&#xD;
             likely to interfere with the subject's ability to give informed consent or participate&#xD;
             in the study.&#xD;
&#xD;
         19. Have concurrent malignancy other than lymphoma; subjects must have been free of other&#xD;
             malignancies for ≥1 year before the start of study treatment. However, subjects with&#xD;
             the following history/concurrent conditions are allowed:&#xD;
&#xD;
               1. Basal or squamous cell carcinoma of the skin&#xD;
&#xD;
               2. Carcinoma in situ of the cervix&#xD;
&#xD;
               3. Carcinoma in situ of the breast&#xD;
&#xD;
               4. Incidental histologic finding of prostate cancer.&#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>Yale Cancer Center</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06519</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68198</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weill Cornell Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Cancer Care Alliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</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>February 6, 2019</study_first_submitted>
  <study_first_submitted_qc>February 7, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</study_first_posted>
  <last_update_submitted>August 21, 2020</last_update_submitted>
  <last_update_submitted_qc>August 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Lymphoma</keyword>
  <keyword>DHODH</keyword>
  <keyword>Hodgkins Lymphoma</keyword>
  <keyword>Non-Hodgkins Lymphoma</keyword>
  <keyword>T-Cell Lymphoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <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/NCT03834584
org study id: AG636-C-001
nct id: NCT03834584
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical
      activity of AG-636, an oral Dihydroorotate Dehydrogenase (DHODH) inhibitor, in subjects with
      advanced lymphoma.
The purpose of this Phase 1, multicenter, open-label study is to determine the maximum
      tolerated dose (MTD) of AG-636 and characterize its dose-limiting toxicities (DLTs) when
      given by mouth to subjects with advanced lymphoma that is refractory to standard treatment.
      During the dose escalation part of the study successive cohorts of subjects will be treated
      with increasing doses of AG-636 in order to determine its maximum tolerated dose (MTD).
      Subsequently, in the dose expansion part of the study, additional subjects will be treated at
      the MTD in order to confirm that dose's safety, tolerability, PK and PD, and to provide an
      opportunity to detect anti-lymphoma activity. The dose expansion part of the study will
      support the selection of a dose for future clinical studies (a recommended Phase 2 dose
      [RP2D]).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The frequency of dose limiting toxicities (DLTs) associated with AG-636 administration during the first cycle (first 28 days) of treatment.
time frame: Up to 28 days, on average
measure: Characterize the Safety and Tolerability of AG-636 (number of treatment-related Adverse Events and Serious Adverse Events)
time frame: Up to 24 weeks, on average
description: As determined by the number of treatment-related Adverse Events and Serious Adverse Events
measure: Characterize the Pharmacodynamics of AG-636
time frame: Up to 24 weeks, on average
description: Measured by changes from baseline in circulating upstream metabolites
measure: Pharmacokinetics of AG-636 in plasma
time frame: Up to 24 weeks, on average
description: Determined by the plasma concentration versus time profile of AG-636
measure: Clinical activity of AG-636 in Lymphoma
time frame: Up to 24 weeks, on average
description: Assessed by either the Lugano criteria for lymphoma or the 2011 International Society for Cutaneous Lymphomas (ISCL)/United States Cutaneous Lymphoma Consortium (USCLC)/ European Organization for Research and Treatment of Cancer (EORTC) criteria for mycosis fungoides (MF)/Sézary syndrome (SS)
arm group label: AG-636
arm group type: Experimental
description: AG-636 dosed orally.
intervention type: Drug
intervention name: AG-636
description: AG-636 will be administered orally intermittently in 28-day cycles.
arm group label: AG-636
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
sharing ipd: No