<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/NCT04496349</url>
  </required_header>
  <id_info>
    <org_study_id>APG115TU101</org_study_id>
    <nct_id>NCT04496349</nct_id>
  </id_info>
  <brief_title>A Study Evaluating APG-115 as a Single Agent or in Combination With APG-2575 in Subjects With T-PLL</brief_title>
  <official_title>A Phase IIa Study Evaluating the Pharmacokinetics, Safety and Efficacy of APG-115 as a Single Agent or in Combination With APG-2575 in Subjects With Relapsed/Refractory T-cell Prolymphocytic Leukemia (R/R T-PLL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ascentage Pharma Group Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ascentage Pharma Group 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 is a multi-center, open-label, phase IIa study to evaluate the pharmacokinetics (PK),&#xD;
      safety, and efficacy of APG-115 as a single agent or in combination with APG-2575 in patients&#xD;
      with T-PLL. The study consists of two parts. A total of 24-36 T-PLL patients will be&#xD;
      enrolled.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In Part 1, 12-18 participants will be enrolled using a 3+3 dose escalation design. Patients&#xD;
      receive APG-115 orally once every day (QD) with meal on Days 1 to 5, and 23 days off in the&#xD;
      28-day cycles.&#xD;
&#xD;
      In Part 2, patients receive APG-115 orally QD on Days 1 to 5, followed by 23 days off in a&#xD;
      28-day cycle. APG-115 dose escalation will use a standard 3+3 design starting from 150 mg,&#xD;
      followed by 200 mg, then 250 mg. APG-2575 will be administered at 800 mg after ramp-up&#xD;
      period. To prevent tumor lysis syndrome (TLS), APG-2575 needs to follow a 3-day daily ramp-up&#xD;
      schedule from 200 mg before the fixed dose 800 mg is reached.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 12, 2021</start_date>
  <completion_date type="Anticipated">May 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The study consists of Part 1 APG-115 as monotherapy and Part 2 APG-2575 in combination with APG-115. APG-115 and APG-2575 will be orally administrated on 28-day cycles. Totally 12-18 participants will be enrolled using a 3+3 dose escalation design in each part. Patients receive APG-115 orally once every day (QD) with meal on Days 1 to 5, 23 days off on the 28-day cycles.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose of APG-115</measure>
    <time_frame>28 days</time_frame>
    <description>To evaluate the safety of APG-115 as a single agent</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum tolerated dose of APG-115+APG-2575</measure>
    <time_frame>28 days</time_frame>
    <description>To evaluate the maximum tolerated dose of APG-115 and APG-2575 in combination</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>T-Prolymphocytic Leukemia</condition>
  <arm_group>
    <arm_group_label>APG-115 monotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>APG-115 will be given alone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>APG-115 + APG-2575 combination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>APG-115 is given in combination with APG-2575</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APG-115</intervention_name>
    <description>APG-115 given orally for first 5 consecutive days each cycle</description>
    <arm_group_label>APG-115 + APG-2575 combination</arm_group_label>
    <arm_group_label>APG-115 monotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APG-2575</intervention_name>
    <description>APG-2575 given orally each day in cycle</description>
    <arm_group_label>APG-115 + APG-2575 combination</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years old&#xD;
&#xD;
          2. Patients with relapsed/refractory T-PLL who have active disease and have received at&#xD;
             least one prior therapy&#xD;
&#xD;
          3. Patients must not have had chemotherapy or antibody therapy for 7 days prior to&#xD;
             starting APG-115 and/or APG-2575. However, patients with rapidly proliferative disease&#xD;
             may receive hydroxyurea or decadron until 24 hours prior to starting therapy on this&#xD;
             protocol.&#xD;
&#xD;
          4. Absolute neutrophil count (ANC) ≥ 500/mm˄3; hemoglobin ≥ 60 g/L; platelet count ≥&#xD;
             30,000/mm˄3&#xD;
&#xD;
          5. Total bilirubin ≤ 1.5 × upper limit of normal (ULN), unless related to leukemic&#xD;
             involvement&#xD;
&#xD;
          6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3× ULN or ≤ 5&#xD;
             × ULN unless related to leukemic involvement&#xD;
&#xD;
          7. Adequate kidney function, defined as a calculated creatinine clearance ≥ 50 mL/min;&#xD;
             determined via urine collection for 24-hour creatinine clearance or by the Cockcroft&#xD;
             Gault formula&#xD;
&#xD;
          8. Require laboratory TLS parameters to be within acceptable range and clinical TLS&#xD;
             parameters no higher than grade 2 at study baseline, with or without TLS treatment,&#xD;
             before initiation of study treatment.&#xD;
&#xD;
          9. Known cardiac ejection fraction of ≥ 45% within the past 3 months, no need to perform&#xD;
             again at screening if this can be found in medical documents&#xD;
&#xD;
         10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2&#xD;
&#xD;
         11. Has no malignancies other than T-PLL that: 1) currently require systemic therapies; 2)&#xD;
             were not previously treated with curative intention (unless the malignant disease is&#xD;
             in a stable remission according to the discretion of the treating physician); 3) or&#xD;
             developed signs of progression after curative treatment&#xD;
&#xD;
         12. A negative serum pregnancy test is required within 1 week for all women of&#xD;
             childbearing potential prior to enrolling in this trial. Women of childbearing&#xD;
             potential and men must agree to use contraception prior to study entry and for the&#xD;
             duration of study participation.&#xD;
&#xD;
         13. Patient must have the ability to understand the requirements of the study and signed&#xD;
             informed consent. A signed informed consent by the patient or his/her legally&#xD;
             authorized representative is required prior to their enrollment on the protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Uncontrolled intercurrent illness including, but not limited to active uncontrolled&#xD;
             infection, symptomatic congestive heart failure (New York Heart Association [NYHA]&#xD;
             class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia,&#xD;
             or psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          2. Patient with documented hypersensitivity to any of the components of the therapy&#xD;
             program.&#xD;
&#xD;
          3. Patient previously treated with a murine double minute 2 (MDM2) inhibitor.&#xD;
&#xD;
          4. Known active, uncontrolled central nervous system (CNS) malignancy&#xD;
&#xD;
          5. Patients require graft versus host therapy, or require continued treatment with&#xD;
             systemic immunosuppressive agents (calcineurin inhibitors within 4 weeks prior to the&#xD;
             first dose of study drug).&#xD;
&#xD;
          6. Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies)&#xD;
&#xD;
          7. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires&#xD;
             treatment or at risk for HBV reactivation. Hepatitis B virus deoxyribonucleic acid&#xD;
             (DNA) and HCV ribonucleic acid (RNA) must be undetectable upon testing. At risk for&#xD;
             HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis&#xD;
             B core antibody positive. Prior test results obtained as part of standard of care that&#xD;
             confirm a subject is immune and not at risk for reactivation (i.e., hepatitis B&#xD;
             surface antigen negative, surface antibody positive) may be used for purposes of&#xD;
             eligibility and tests do not need to be repeated. Subjects with prior positive&#xD;
             serology results must have negative polymerase chain reaction results. Subjects whose&#xD;
             immune status is unknown or uncertain must have results confirming immune status&#xD;
             before enrollment.&#xD;
&#xD;
          8. Patients with COVID-19 who are tested with positive swab.&#xD;
&#xD;
          9. Failure to have recovered (Grade &gt; 1) (except alopecia and pigmentation) from prior&#xD;
             treatment (including chemotherapy, targeted therapy, immunotherapy, experimental&#xD;
             agents, radiation, or surgery)&#xD;
&#xD;
         10. Significant screening electrocardiogram (ECG) abnormalities including corrected QT&#xD;
             interval (Fridericia) (QTcF) &gt; 470 msec&#xD;
&#xD;
         11. Patients who have any conditions or illness that, according to the opinions of the&#xD;
             Investigators or the medical monitor, would compromise patient safety or interfere&#xD;
             with the evaluation of safety and efficacy to the study drug(s).&#xD;
&#xD;
         12. Patients who have used strong CYP2C8 inhibitors, or moderate or strong CYP3A4&#xD;
             inhibitors or inducers within washout period of 14 days or 7 half-lives before the&#xD;
             first administration of study drugs, whichever is longer.&#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>Yifan Zhai, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Ascentage Pharma Group Inc.</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Angela Kaiser</last_name>
    <phone>301-509-0357</phone>
    <email>Angela.Kaiser@ascentage.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>City of Hope</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melissa Banez</last_name>
      <phone>626-218-8276</phone>
      <email>mbanez@coh.org</email>
    </contact>
    <investigator>
      <last_name>Geoffrey Shouse, DO, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hemalatha Rao</last_name>
      <phone>614-685-1976</phone>
      <email>Hemalatha.Rao@osumc.edu</email>
    </contact>
    <investigator>
      <last_name>Jonathan Brammer, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>MD Anderson</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kelly Quagliato</last_name>
      <phone>713-614-2069</phone>
      <email>krquagliato@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Tapan Kadia, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <last_update_submitted>July 8, 2022</last_update_submitted>
  <last_update_submitted_qc>July 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2022</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>Leukemia</mesh_term>
    <mesh_term>Leukemia, Prolymphocytic</mesh_term>
    <mesh_term>Leukemia, Prolymphocytic, T-Cell</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/NCT04496349
org study id: APG115TU101
nct id: NCT04496349
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a multi-center, open-label, phase IIa study to evaluate the pharmacokinetics (PK),
      safety, and efficacy of APG-115 as a single agent or in combination with APG-2575 in patients
      with T-PLL. The study consists of two parts. A total of 24-36 T-PLL patients will be
      enrolled.
In Part 1, 12-18 participants will be enrolled using a 3+3 dose escalation design. Patients
      receive APG-115 orally once every day (QD) with meal on Days 1 to 5, and 23 days off in the
      28-day cycles.

      In Part 2, patients receive APG-115 orally QD on Days 1 to 5, followed by 23 days off in a
      28-day cycle. APG-115 dose escalation will use a standard 3+3 design starting from 150 mg,
      followed by 200 mg, then 250 mg. APG-2575 will be administered at 800 mg after ramp-up
      period. To prevent tumor lysis syndrome (TLS), APG-2575 needs to follow a 3-day daily ramp-up
      schedule from 200 mg before the fixed dose 800 mg is reached.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: The study consists of Part 1 APG-115 as monotherapy and Part 2 APG-2575 in combination with APG-115. APG-115 and APG-2575 will be orally administrated on 28-day cycles. Totally 12-18 participants will be enrolled using a 3+3 dose escalation design in each part. Patients receive APG-115 orally once every day (QD) with meal on Days 1 to 5, 23 days off on the 28-day cycles.
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of APG-115
time frame: 28 days
description: To evaluate the safety of APG-115 as a single agent
measure: Maximum tolerated dose of APG-115+APG-2575
time frame: 28 days
description: To evaluate the maximum tolerated dose of APG-115 and APG-2575 in combination
arm group label: APG-115 monotherapy
arm group type: Experimental
description: APG-115 will be given alone
arm group label: APG-115 + APG-2575 combination
arm group type: Experimental
description: APG-115 is given in combination with APG-2575
intervention type: Drug
intervention name: APG-115
description: APG-115 given orally for first 5 consecutive days each cycle
arm group label: APG-115 + APG-2575 combination
arm group label: APG-115 monotherapy
intervention type: Drug
intervention name: APG-2575
description: APG-2575 given orally each day in cycle
arm group label: APG-115 + APG-2575 combination
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Yifan Zhai, MD, PhD
role: Study Chair
affiliation: Ascentage Pharma Group Inc.
last name: Angela Kaiser
phone: 301-509-0357
email: Angela.Kaiser@ascentage.com
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Prolymphocytic
mesh term: Leukemia, Prolymphocytic, T-Cell
sharing ipd: No