<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/NCT03295396</url>
  </required_header>
  <id_info>
    <org_study_id>ONC013</org_study_id>
    <nct_id>NCT03295396</nct_id>
  </id_info>
  <brief_title>ONC201 in Adults With Recurrent H3 K27M-mutant Glioma</brief_title>
  <official_title>A Phase II, Open-label Study of ONC201 in Adults With Recurrent High-grade Glioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chimerix</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chimerix</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 primary objective of this phase II trial is to determine the efficacy and safety of&#xD;
      ONC201, an oral small molecule imipridone DRD2 antagonist, in adult subjects with recurrent&#xD;
      high-grade glioma. This study will test the research hypothesis that histone H3 K27M mutation&#xD;
      sensitizes to oral administration of ONC201 in gliomas.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 31, 2017</start_date>
  <completion_date type="Anticipated">September 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 30, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</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</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Best overall response rate by RANO</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">95</enrollment>
  <condition>Glioma</condition>
  <arm_group>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ONC201 in relapsed H3 K27M glioma</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ONC201 in relapsed H3 K27M glioma, excluding:&#xD;
Primary malignant lesion located in the pons or spinal cord.&#xD;
Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA).&#xD;
Prior bevacizumab treatment of &gt;4 doses of &gt;7.5 mg/Kg&#xD;
Tumors with known 1p/19q co-deletion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ONC201</intervention_name>
    <description>ONC201 is an oral, small molecule selective antagonist of DRD2 that induces tumor cell death.</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed diagnosis of high-grade glioma (HGG) in any tumor sample and&#xD;
             presence of histone H3 K27M mutation detected in a Clinical Laboratory Improvement&#xD;
             Amendment (CLIA) certified laboratory by immunohistochemistry or DNA sequencing test&#xD;
             on any glioma tumor sample.&#xD;
&#xD;
          2. Unequivocal evidence of progressive disease on contrast-enhanced brain CT or MRI as&#xD;
             defined by RANO-HGG criteria, or have documented recurrent glioma on diagnostic&#xD;
             biopsy.&#xD;
&#xD;
          3. Measurable disease by RANO-HGG criteria.&#xD;
&#xD;
          4. Patients must have had previous therapy with at least radiotherapy.&#xD;
&#xD;
          5. No more than two prior episodes of recurrence from radiotherapy and/or chemotherapy.&#xD;
             Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or&#xD;
             treatment effect will not be considered a recurrence.&#xD;
&#xD;
          6. Interval of at least 90 days from the completion of radiotherapy to the first dose of&#xD;
             ONC201. If patients are within 90 days of radiotherapy, they may still be eligible if&#xD;
             they meet one or more of the following criteria.&#xD;
&#xD;
               1. Progressive tumor is outside the original high-dose radiotherapy target volume as&#xD;
                  determined by the treating investigator, or&#xD;
&#xD;
               2. Histologic confirmation of tumor through biopsy or resection, or&#xD;
&#xD;
               3. Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistent&#xD;
                  with true progressive disease, rather than pseudoprogression or radiation&#xD;
                  necrosis obtained within 28 days of registration.&#xD;
&#xD;
          7. From the projected start of scheduled study treatment, the following time periods must&#xD;
             have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic&#xD;
             therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from&#xD;
             antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor&#xD;
             therapies.&#xD;
&#xD;
          8. All adverse events Grade &gt; 1 related to prior therapies (chemotherapy, radiotherapy,&#xD;
             and/or surgery) must be resolved to grade 1 or baseline, except for alopecia and&#xD;
             sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based&#xD;
             on investigator's judgment, are acceptable.&#xD;
&#xD;
          9. Male or Female age ≥18 years.&#xD;
&#xD;
         10. Karnofsky Performance Status (KPS) ≥ 60 (see Appendix A).&#xD;
&#xD;
         11. Adequate organ and marrow function as defined below, all screening labs should be&#xD;
             performed within 14 days of treatment initiation:&#xD;
&#xD;
               -  leukocytes ≥ 3,000/mcL&#xD;
&#xD;
               -  absolute neutrophil count ≥ 1,500/mcL&#xD;
&#xD;
               -  platelets ≥ 75,000/mcL&#xD;
&#xD;
               -  hemoglobin &gt; 8.0 mg/dL&#xD;
&#xD;
               -  total bilirubin ≤ 2.0 x upper limit of normal&#xD;
&#xD;
               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 × upper limit of normal&#xD;
&#xD;
               -  creatinine ≤ ULN OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with&#xD;
                  creatinine levels above normal.&#xD;
&#xD;
         12. Contrast-enhanced head CT or brain MRI and entire spine MRI within 14 days prior to&#xD;
             start of study drug.&#xD;
&#xD;
         13. Corticosteroid dose must be stable or decreasing for at least 3 days prior to the&#xD;
             baseline CT or MRI scan.&#xD;
&#xD;
         14. The effects of ONC201 on the developing human fetus are unknown. For this reason,&#xD;
             women of childbearing potential (WOCBP) and men must agree to use adequate&#xD;
             contraception prior to study entry and for the duration of study participation and for&#xD;
             30 days after the last dose of therapy. Highly effective contraceptive measures&#xD;
             include: stable use of oral contraceptives such as combined estrogen and progestogen&#xD;
             and progestogen only hormonal contraception or other prescription pharmaceutical&#xD;
             contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device&#xD;
             [IUD]; intrauterine hormone- releasing system (IUS); bilateral tubal ligation;&#xD;
             vasectomy and sexual abstinence.&#xD;
&#xD;
               1. WOCBP must have a negative serum or urine pregnancy test within 28 days of&#xD;
                  initiation of dosing.&#xD;
&#xD;
               2. Contraception is not required for men with documented vasectomy.&#xD;
&#xD;
               3. Postmenopausal women must be amenorrheic for at least 12 months in order not to&#xD;
                  be considered of childbearing potential.&#xD;
&#xD;
               4. Pregnancy testing and contraception are not required for women with documented&#xD;
                  hysterectomy or tubal ligation.&#xD;
&#xD;
         15. Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1&#xD;
             cm2 of tumor surface area, or 20 unstained slides from the tumor tissue specimen if a&#xD;
             tumor block cannot be submitted. If a patient has had only a stereotactic biopsy, then&#xD;
             5 unstained slides may be accepted with prior approval from the Sponsor, however all&#xD;
             efforts must be made to obtain as close to 20 slides as possible.&#xD;
&#xD;
         16. Ability to be able to swallow and retain orally administered medication&#xD;
&#xD;
         17. Ability to understand and the willingness to sign a written informed consent document.&#xD;
             Only subjects who have capacity to consent will be enrolled in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Arm B: Primary malignant lesion located in the pons or spinal cord.&#xD;
&#xD;
          2. Arm B: Atypical non-astrocytic histologies such as ependymoma, ganglioma and&#xD;
             pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell&#xD;
             astrocytoma (SEGA).&#xD;
&#xD;
          3. Arm B: Prior bevacizumab treatment of &gt;4 doses of &gt;7.5 mg/Kg&#xD;
&#xD;
          4. History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to ONC201 or its excipients (See Section 8).&#xD;
&#xD;
          5. Current or planned participation in a study of an investigational agent or using an&#xD;
             investigational device.&#xD;
&#xD;
          6. Presence of diffuse leptomeningeal disease or evidence of CSF dissemination.&#xD;
&#xD;
          7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          8. Active infection requiring systemic therapy.&#xD;
&#xD;
          9. Pregnant and/or breastfeeding women or unable to maintain use of contraception while&#xD;
             on study and for 30 days after the last dose of study drug. ONC201 is a novel agent&#xD;
             with unknown potential for teratogenic or abortifacient effects. Because there is an&#xD;
             unknown but potential risk for adverse events in nursing infants, secondary to&#xD;
             treatment of the mother with ONC201, breastfeeding should be discontinued if the&#xD;
             mother is treated with ONC201.&#xD;
&#xD;
         10. Known HIV-positive test on combination antiretroviral therapy.&#xD;
&#xD;
         11. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias&#xD;
             or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared&#xD;
             patient to receive ONC 201. Receiving therapeutic agents known to prolong QT interval&#xD;
             will be excluded. History of CHF, or MI or stroke in the last 3 months will be&#xD;
             excluded.&#xD;
&#xD;
         12. Active illicit drug use or diagnosis of alcoholism.&#xD;
&#xD;
         13. Tumors with known IDH1 (isocitrate dehydrogenase 1) or known IDH2 mutations as&#xD;
             determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing.&#xD;
             IDH1/2-mutant gliomas have a markedly longer overall survival rate compared to those&#xD;
             with IDH1/2-wildtype glioma (Parsons et al., 2008; Yan et al., 2009), indicating&#xD;
             IDH1/2-mutant gliomas have a distinct natural history.&#xD;
&#xD;
         14. Tumors with known 1p/19q co-deletion.&#xD;
&#xD;
         15. Known additional malignancy that is progressing or requires active treatment within 3&#xD;
             years of start of study drug. Exceptions include basal cell carcinoma of the skin,&#xD;
             squamous cell carcinoma of the skin, in situ melanoma, or in situ cervical cancer that&#xD;
             has undergone potentially curative therapy.&#xD;
&#xD;
         16. Any surgery (not including minor diagnostic procedures such as lymph node biopsy)&#xD;
             within 2 weeks of baseline disease assessments; or not fully recovered from any side&#xD;
             effects of previous procedures. An interval of 1 week for stereotactic brain biopsy&#xD;
             from the start of study treatment is acceptable.&#xD;
&#xD;
         17. Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study&#xD;
             and within 72 hours prior to starting study drug administration.&#xD;
&#xD;
         18. Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing&#xD;
             antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the study&#xD;
             and within 2 weeks prior to starting treatment. Concurrent dexamethasone is allowed.&#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>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143-0112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford Cancer Center</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York University School of Medicine</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Levine Cancer Institute</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital of the University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</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_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>August 11, 2023</last_update_submitted>
  <last_update_submitted_qc>August 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2023</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>Glioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>TIC10 compound</mesh_term>
  </intervention_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/NCT03295396
org study id: ONC013
nct id: NCT03295396
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The primary objective of this phase II trial is to determine the efficacy and safety of
      ONC201, an oral small molecule imipridone DRD2 antagonist, in adult subjects with recurrent
      high-grade glioma. This study will test the research hypothesis that histone H3 K27M mutation
      sensitizes to oral administration of ONC201 in gliomas.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate
time frame: Through study completion, an average of 1 year
description: Best overall response rate by RANO
arm group label: Arm A
arm group type: Experimental
description: ONC201 in relapsed H3 K27M glioma
arm group label: Arm B
arm group type: Experimental
description: ONC201 in relapsed H3 K27M glioma, excluding:
Primary malignant lesion located in the pons or spinal cord.
Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA).
Prior bevacizumab treatment of >4 doses of >7.5 mg/Kg
Tumors with known 1p/19q co-deletion.
intervention type: Drug
intervention name: ONC201
description: ONC201 is an oral, small molecule selective antagonist of DRD2 that induces tumor cell death.
arm group label: Arm A
arm group label: Arm B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Glioma
mesh term: TIC10 compound
sharing ipd: Undecided