<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/NCT03760523</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-19742</org_study_id>
    <nct_id>NCT03760523</nct_id>
  </id_info>
  <brief_title>Dose Escalation Study of Minnelide in Relapsed or Refractory Acute Myeloid Leukemia</brief_title>
  <official_title>Phase 1/1b Dose Escalation Study of Minnelide in Relapsed or Refractory Acute Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>H. Lee Moffitt Cancer Center and Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Minneamrita Therapeutics LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>H. Lee Moffitt Cancer Center and Research Institute</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 is to determine the safety and recommended dosing of Minnelide in Acute Myeloid&#xD;
      Leukemia (AML)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This phase 1 dose escalation clinical trial will establish the maximum tolerated dose (MTD)&#xD;
      and recommended phase 2 dose (RP2D) of Minnelide as single-agent in relapsed/refractory (R/R)&#xD;
      acute myeloid leukemia (AML) patients who are ineligible to receive intensive chemotherapy.&#xD;
      The oral formulation of Minnelide will be used. Minnelide is a prodrug of triptolide (a&#xD;
      potent heat shock protein (HSP) 70 inhibitor) with promising preclinical activity in AML.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 18, 2019</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <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>Maximum Tolerated Dose (MTD) of Minnelide</measure>
    <time_frame>Up to 28 days for each dosing cohort</time_frame>
    <description>MTD will be determined by testing increasing doses up to 1.25 mg daily. MTD reflects highest dose of drug that did not cause a Dose Limiting Toxicity (DLT).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants Who Experience Dose Limiting Toxicities (DLTs)</measure>
    <time_frame>Up to 28 days for each dosing cohort</time_frame>
    <description>A DLT is any Grade 3 or 4 drug-related non-hematologic toxicity, with some exceptions per protocol.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Complete Response (CR)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Participants who experience Complete Response (CR) and Complete Response with Incomplete Blood Count Recovery (CRi) rate as defined by 2003 International Working Group (IWG) for AML.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Overall Response Rate is defined as CR + CRi + partial response (PR) as defined by 2003 IWG criteria for AML.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse Free Survival (RFS)</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>RFS is defined as time interval between achievement of CR to time of relapse.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>OS defined as time interval from time of enrollment onto the clinical trial to death from any cause.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">28</enrollment>
  <condition>Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Minnelide Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A 3+3 design will be used. The first 3 patients will be treated at dose level 1. If none experience a Dose Limiting Toxicity (DLT), the next 3 patients will be treated at dose level 2. If a DLT is observed in 1 out of 3 patients at dose level 1, up to an 3 more patients will be enrolled and treated at that dose level. If 2 patients at dose level have DLTs, dosing will be lowered to dose level -1 (.5 mg daily, taken orally). If 2 or more of the up to 6 patients at any dose level have DLTs, the preceding dose will be declared the Maximum Tolerated Dose (MTD). If more than 1 DLT occurs at Dose Level -1, the investigators will consider stopping the study. Once the MTD has been established, an additional 10 patients will be enrolled at this level to better characterize safety and tolerability.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Minnelide</intervention_name>
    <description>Patients will take Minnelide orally once daily on Days 1-21 of 28 day Cycle. Dose Escalation Schedule: Dose Level -1: .5 mg, Dose Level 1: .75 mg, Dose Level 2: 1 mg, Dose Level 3: 1.25 mg.</description>
    <arm_group_label>Minnelide Dose Escalation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults ages 18 years or older.&#xD;
&#xD;
          -  Participant must have relapsed or refractory acute myeloid leukemia (AML) (excluding&#xD;
             acute promyelocytic leukemia).&#xD;
&#xD;
          -  Relapsed patients must have received at least 1 induction chemotherapy regimen or two&#xD;
             cycles of a hypomethylating agent and achieved a Complete Response (CR), followed by&#xD;
             relapse of disease.&#xD;
&#xD;
          -  Refractory patients must have received at least 1 induction chemotherapy regimen or&#xD;
             two cycles of hypomethylating agent without achieving a CR.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status &lt;2.&#xD;
&#xD;
          -  Participants must have acceptable organ function.&#xD;
&#xD;
          -  Be able and willing to adhere to the study visit schedule and other protocol&#xD;
             requirements.&#xD;
&#xD;
          -  Must be able to swallow capsules and have no evidence of GI tract abnormality that&#xD;
             would alter the absorption of oral medications.&#xD;
&#xD;
          -  The effects of Minnelide on the developing human fetus are unknown. For this reason,&#xD;
             women of child-bearing potential must have a negative serum or urine pregnancy test&#xD;
             within 24 hours prior to beginning study treatment.&#xD;
&#xD;
          -  Participants of childbearing potential must practice contraception. Females of&#xD;
             childbearing potential: Recommendation is for 2 effective contraceptive methods during&#xD;
             the study. Male participants with female partners who are of childbearing potential:&#xD;
             Recommendation is for male and partner to use at least 2 effective contraceptive&#xD;
             methods, as described above, during the study. Should a woman become pregnant or&#xD;
             suspect she is pregnant while participating in this study, she should inform her&#xD;
             treating physician immediately.&#xD;
&#xD;
          -  Because there is an unknown but potential risk for adverse events in nursing infants&#xD;
             secondary to treatment of the mother with Minnelide, breastfeeding mothers must agree&#xD;
             to discontinue nursing if the mother is treated with Minnelide.&#xD;
&#xD;
          -  Provision of signed and dated informed consent document&#xD;
&#xD;
          -  Patients with prior allogeneic stem cell transplant who experience relapse of AML are&#xD;
             eligible if they are off of immunosuppressive therapy and without any evidence of&#xD;
             graft-versus-host disease (GVHD)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants may not have received any therapy with any investigational products,&#xD;
             systemic anti-neoplastic therapy, or radiotherapy within 14 days prior to Cycle 1 Day&#xD;
             1. Patients actively receiving hydroxyurea are eligible and may continue to receive&#xD;
             hydroxyurea during protocol treatment.&#xD;
&#xD;
          -  Candidates for standard and/or potentially curative treatments.&#xD;
&#xD;
          -  Major surgery within 28 days prior to Cycle 1 Day 1.&#xD;
&#xD;
          -  New York Heart Association Class III or IV heart failure, myocardial infarction within&#xD;
             the past 6 months, unstable arrhythmia, or evidence of ischemia on an&#xD;
             electrocardiogram (EKG)&#xD;
&#xD;
          -  Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic&#xD;
             therapy&#xD;
&#xD;
          -  Known, active HIV, Hepatitis A, B or C infection (prior Hepatitis C infection that has&#xD;
             been treated and determined to be cured is allowed)&#xD;
&#xD;
          -  Symptomatic central nervous system (CNS) involvement with leukemia&#xD;
&#xD;
          -  A concurrent second active and non-stable malignancy with the exception of&#xD;
             non-melanoma skin cancer or carcinoma in-situ.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zhuoer Xie, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>H. Lee Moffitt Cancer Center and Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>H. Lee Moffitt Cancer Center and Research Institute</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maha Balouch</last_name>
      <phone>813-745-8650</phone>
      <email>Maha.Balouch@moffitt.org</email>
    </contact>
    <investigator>
      <last_name>David Sallman, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jeffrey Lancet, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Rami Komrokji, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Mohammad Hussaini, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Eric Padron, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://moffitt.org/clinical-trials-research/clinical-trials/</url>
    <description>Moffitt Cancer Center Clinical Trials Website</description>
  </link>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>November 27, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <last_update_submitted>July 7, 2023</last_update_submitted>
  <last_update_submitted_qc>July 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>leukemia</keyword>
  <keyword>myeloid leukemia</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>14-O-phosphonooxymethyltriptolide disodium salt</mesh_term>
  </intervention_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/NCT03760523
org study id: MCC-19742
nct id: NCT03760523
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This study is to determine the safety and recommended dosing of Minnelide in Acute Myeloid
      Leukemia (AML)
This phase 1 dose escalation clinical trial will establish the maximum tolerated dose (MTD)
      and recommended phase 2 dose (RP2D) of Minnelide as single-agent in relapsed/refractory (R/R)
      acute myeloid leukemia (AML) patients who are ineligible to receive intensive chemotherapy.
      The oral formulation of Minnelide will be used. Minnelide is a prodrug of triptolide (a
      potent heat shock protein (HSP) 70 inhibitor) with promising preclinical activity in AML.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Minnelide
time frame: Up to 28 days for each dosing cohort
description: MTD will be determined by testing increasing doses up to 1.25 mg daily. MTD reflects highest dose of drug that did not cause a Dose Limiting Toxicity (DLT).
measure: Number of Participants Who Experience Dose Limiting Toxicities (DLTs)
time frame: Up to 28 days for each dosing cohort
description: A DLT is any Grade 3 or 4 drug-related non-hematologic toxicity, with some exceptions per protocol.
measure: Complete Response (CR)
time frame: Up to 12 months
description: Participants who experience Complete Response (CR) and Complete Response with Incomplete Blood Count Recovery (CRi) rate as defined by 2003 International Working Group (IWG) for AML.
measure: Overall Response Rate (ORR)
time frame: Up to 12 months
description: Overall Response Rate is defined as CR + CRi + partial response (PR) as defined by 2003 IWG criteria for AML.
measure: Relapse Free Survival (RFS)
time frame: Up to 18 months
description: RFS is defined as time interval between achievement of CR to time of relapse.
measure: Overall Survival (OS)
time frame: Up to 12 months
description: OS defined as time interval from time of enrollment onto the clinical trial to death from any cause.
arm group label: Minnelide Dose Escalation
arm group type: Experimental
description: A 3+3 design will be used. The first 3 patients will be treated at dose level 1. If none experience a Dose Limiting Toxicity (DLT), the next 3 patients will be treated at dose level 2. If a DLT is observed in 1 out of 3 patients at dose level 1, up to an 3 more patients will be enrolled and treated at that dose level. If 2 patients at dose level have DLTs, dosing will be lowered to dose level -1 (.5 mg daily, taken orally). If 2 or more of the up to 6 patients at any dose level have DLTs, the preceding dose will be declared the Maximum Tolerated Dose (MTD). If more than 1 DLT occurs at Dose Level -1, the investigators will consider stopping the study. Once the MTD has been established, an additional 10 patients will be enrolled at this level to better characterize safety and tolerability.
intervention type: Drug
intervention name: Minnelide
description: Patients will take Minnelide orally once daily on Days 1-21 of 28 day Cycle. Dose Escalation Schedule: Dose Level -1: .5 mg, Dose Level 1: .75 mg, Dose Level 2: 1 mg, Dose Level 3: 1.25 mg.
arm group label: Minnelide Dose Escalation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Zhuoer Xie, MD
role: Principal Investigator
affiliation: H. Lee Moffitt Cancer Center and Research Institute
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: United States
url: http://moffitt.org/clinical-trials-research/clinical-trials/
description: Moffitt Cancer Center Clinical Trials Website
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: 14-O-phosphonooxymethyltriptolide disodium salt