<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/NCT03760445</url>
  </required_header>
  <id_info>
    <org_study_id>CHDM201A2101</org_study_id>
    <secondary_id>2018-003107-19</secondary_id>
    <nct_id>NCT03760445</nct_id>
  </id_info>
  <brief_title>HDM201 Added to CT in R/R or Newly Diagnosed AML</brief_title>
  <official_title>A Phase I/II Multi-center Study of HDM201 Added to Chemotherapy in Adult Subjects With Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</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 I/II study investigating orally administered HDM201&#xD;
      in combination with chemotherapy in two populations: subjects with first line AML or subjects&#xD;
      with relapsed/refractory AML. This study is conducted in three parts: dose escalation, dose&#xD;
      expansion and DDI study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 1 / 2 study. No patients were screened / enrolled. There are no data&#xD;
      collected. There will be no CSR.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    It was determined that the study design may not be optimal given the changing AML treatment&#xD;
    landscape.&#xD;
  </why_stopped>
  <start_date type="Anticipated">November 15, 2019</start_date>
  <completion_date type="Anticipated">June 13, 2023</completion_date>
  <primary_completion_date type="Anticipated">July 22, 2021</primary_completion_date>
  <phase>Phase 1/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>3 parts - two different populations Part 1 - escalation - parallel dose escalation in 1L AML subjects and in R/R subjects (up to 8 dose cohorts per arm.&#xD;
Part 2 - expansion - parallel expansion in 3 cohorts of 1L AML, and 1 cohort of R/R AML after recommended dose of expansion was determined.&#xD;
Part 3 - DDI - parallel enrollment or R/R AML subjects into 2 DDI Cohorts (one with CYP3A4 inhibitor, one with CYP3A4 substrate).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1 - Incidence of dose limiting toxicity (DLT)</measure>
    <time_frame>first day of study treatment to 3 months after start of study treatment</time_frame>
    <description>number of DLTs by dose regimen of first line (1L) acute myeloid leukemia (AML) subjects during induction treatment; number of DLTs by dose regimen of relapsed/refractory (R/R) AML subjects during treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1 - Time to DLT</measure>
    <time_frame>first day of study treatment to 3 months after start of study treatment</time_frame>
    <description>time from first dose to onset of DLT by dose regimen of 1L AML and R/R AML subjects</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 1 - Incidence and severity of Adverse Events (AEs)</measure>
    <time_frame>first day of study treatment to 3 months after start of study treatment</time_frame>
    <description>number and grade of AEs by dose regimen of 1L AML and R/R AML subjects during DLT observation period</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2 - Incidence and severity of AEs/serious adverse events (SAEs)</measure>
    <time_frame>first day of study treatment until 8.5 months after start of study treatment</time_frame>
    <description>number and grade of AEs/SAEs by expansion cohort</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR)</measure>
    <time_frame>first day of study treatment until 4.5 months after start of study treatment</time_frame>
    <description>Percentage of participants with CR/CRi with ABCR at the end of induction treatment for Expansion Cohort 1, and at the end of treatment for Expansion Cohort 4</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2 - Incidence and severity of abnormal laboratory values</measure>
    <time_frame>first day of study treatment until 8.5 months after start of study treatment</time_frame>
    <description>number and grade of abnormal laboratory results by expansion cohort</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results</measure>
    <time_frame>first day of study treatment until 8.5 months after start of study treatment</time_frame>
    <description>number and severity of abnormal ECG results by expansion cohort</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2 - Incidence and severity of abnormal vital signs</measure>
    <time_frame>first day of study treatment until 8.5 months after start of study treatment</time_frame>
    <description>number and severity of abnormal vital signs by expansion cohort</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC)</measure>
    <time_frame>first day of HDM201 dose to 10 days after start of HDM201</time_frame>
    <description>determine HDM201 AUC from time zero to the last measurable concentration sampling time (AUClast) in Cycle 1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax)</measure>
    <time_frame>first day of HDM201 dose to 10 days after start of HDM201</time_frame>
    <description>determine HDM201 Cmax in Cycle 1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration</measure>
    <time_frame>first day of HDM201 dose to 10 days after start of HDM201</time_frame>
    <description>determine HDM201 average plasma concentration in Cycle 1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax)</measure>
    <time_frame>first day of HDM201 dose to 10 days after start of HDM201</time_frame>
    <description>determine HDM201 Tmax in Cycle 1</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3 - DDI Cohort 2: midazolam PK AUC</measure>
    <time_frame>first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)</time_frame>
    <description>determine midazolam AUC last and AUC from time zero to infinity (inf)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3 - DDI Cohort 2: midazolam PK Cmax</measure>
    <time_frame>first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)</time_frame>
    <description>determine midazolam Cmax</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part 1 +2: HDM201 PK AUC</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1 +2: HDM201 PK Cmax</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>determine Cmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1 +2: HDM201 PK Tmax</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>determine Tmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1 - incidence of AEs/SAEs</measure>
    <time_frame>first day of study treatment to 8.5 months after start of study treatment</time_frame>
    <description>number and grade of AEs/SAEs, by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - all Expansion Cohorts: time to platelet recovery</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>determine time to platelet recovery by Expansion Cohort for each cycle</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - all Expansion Cohorts: time to neutrophil recovery</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>determine time to neutrophil recovery by Expansion Cohort for each cycle</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - all Expansion Cohorts: overall survival</measure>
    <time_frame>first day of study treatment to 3 years after last patient is enrolled to Part 2</time_frame>
    <description>determine overall survival by Expansion Cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - all Expansion Cohorts: event-free survival</measure>
    <time_frame>first day of study treatment to 3 years after last patient is enrolled to Part 2</time_frame>
    <description>determine event-free survival by Expansion Cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT)</measure>
    <time_frame>first day of study treatment to 3 years after last patient was enrolled to Part 2</time_frame>
    <description>percentage of subjects receiving HSCT after study treatment by Expansion Cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS)</measure>
    <time_frame>first day of study treatment to 3 years after last patient enrolled to Part 2</time_frame>
    <description>determine DFS by Expansion Cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR)</measure>
    <time_frame>first day of study treatment to 3 years after last patient enrolled to Part 2</time_frame>
    <description>determine CIR by Expansion Cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>proportion of subjects achieving CR or CRi with ABCR by Expansion Cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity</measure>
    <time_frame>first day of study treatment to 7.5 months after start of study treatment</time_frame>
    <description>proportion of subjects achieving MRD negativity by Expansion Cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - expansion cohort 2: midostaurin PK AUC</measure>
    <time_frame>first day of study treatment to 7.5 month after start of study treatment</time_frame>
    <description>determine midostaurin AUC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - expansion cohort 2: midostaurin PK Cmax</measure>
    <time_frame>first day of study treatment to 7.5 month after start of study treatment</time_frame>
    <description>determine midostaurin Cmax during induction and consolidation treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2 - expansion cohort 2: midostaurin PK Tmax</measure>
    <time_frame>first day of study treatment to 7.5 month after start of study treatment</time_frame>
    <description>determine midostaurin Tmax during induction and consolidation treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1 - incidence of abnormal laboratory values</measure>
    <time_frame>first day of study treatment to 8.5 months after start of study treatment</time_frame>
    <description>number of abnormal laboratory results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1 - incidence of abnormal ECG results</measure>
    <time_frame>first day of study treatment to 8.5 months after start of study treatment</time_frame>
    <description>number of abnormal ECG results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 1 - incidence of abnormal vital signs</measure>
    <time_frame>first day of study treatment to 8.5 months after start of study treatment</time_frame>
    <description>number of abnormal vital signs by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days</description>
  </secondary_outcome>
  <number_of_arms>8</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Leukemia, Myeloid, Acute</condition>
  <arm_group>
    <arm_group_label>Part 1 - first line (1L) AML</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1L acute myeloid leukemia (AML) subjects receiving HDM201 in various doses/schedules in combination with cytarabine/anthracyclines</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1 - relapsed/refractory (R/R) AML</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>R/R AML subjects receiving HDM201 in various doses/schedules in combination with cytarabine</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 - Expansion Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1L de novo AML subjects without documented FLT3 mutation receiving HDM201 at the recommended dose of expansion (RDE) in combination with cytarabine/anthracyclines</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 - Expansion Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1L de novo AML subjects with documented FLT3 mutation status receiving HDM201 at RDE in combination with cytarabine/anthracyclines and midostaurin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 - Expansion Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1L secondary AML subjects receiving HDM201 at RDE in combination with liposomal cytarabine/daunorubicin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 - Expansion Cohort 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>R/R AML subjects receiving HDM201 at RDE in combination with cytarabine</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3 - DDI Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>R/R AML subjects receiving HDM201 at adjusted recommended Phase 3 dose (RP3D) determined in Part 2 in combination with cytarabine and posaconazole added in Cycle 1</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3 - DDI Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>R/R AML subjects receiving HDM201 at RP3D in combination with cytarabine and midazolam</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>HDM201</intervention_name>
    <description>2.5 mg and 10mg capsules, given orally</description>
    <arm_group_label>Part 1 - first line (1L) AML</arm_group_label>
    <arm_group_label>Part 1 - relapsed/refractory (R/R) AML</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 1</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 2</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 3</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 4</arm_group_label>
    <arm_group_label>Part 3 - DDI Cohort 1</arm_group_label>
    <arm_group_label>Part 3 - DDI Cohort 2</arm_group_label>
    <other_name>none available</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cytarabine</intervention_name>
    <description>20mg or 1000 mg or other strengths as locally available given intravenously</description>
    <arm_group_label>Part 1 - first line (1L) AML</arm_group_label>
    <arm_group_label>Part 1 - relapsed/refractory (R/R) AML</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 1</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 2</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 3</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 4</arm_group_label>
    <arm_group_label>Part 3 - DDI Cohort 1</arm_group_label>
    <arm_group_label>Part 3 - DDI Cohort 2</arm_group_label>
    <other_name>Ara-C, Cytosar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>anthracycline</intervention_name>
    <description>20mg or other strength as locally available given intravenously</description>
    <arm_group_label>Part 1 - first line (1L) AML</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 1</arm_group_label>
    <arm_group_label>Part 2 - Expansion Cohort 2</arm_group_label>
    <other_name>daunorubicin or idarubicin, Rubidomycin or Idamycin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>midostaurin</intervention_name>
    <description>25mg capsules given orally</description>
    <arm_group_label>Part 2 - Expansion Cohort 2</arm_group_label>
    <other_name>PKC412, Rydapt</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>liposomal cytarabine/daunorubicin</intervention_name>
    <description>100mg/44mg or other strength as locally available given intravenously</description>
    <arm_group_label>Part 2 - Expansion Cohort 3</arm_group_label>
    <other_name>Vyxeos</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>posaconazole</intervention_name>
    <description>100mg delayed release tablet or other strength as locally available given orally</description>
    <arm_group_label>Part 3 - DDI Cohort 1</arm_group_label>
    <other_name>Noxafil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>midazolam</intervention_name>
    <description>2mg/mL oral solution or in other strength as locally available</description>
    <arm_group_label>Part 3 - DDI Cohort 2</arm_group_label>
    <other_name>midazolam HCl</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All Subjects&#xD;
&#xD;
          -  Signed informed consent must be obtained prior to participation in the study&#xD;
&#xD;
          -  Age ≥18&#xD;
&#xD;
          -  Diagnosis of AML based on WHO 2016 classification. Patients with APL (acute&#xD;
             promyelocytic leukemia) with PML-RARA are not eligible.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) that is 0 - 2.&#xD;
&#xD;
          -  Adequate organ functions&#xD;
&#xD;
          -  Left ventricular ejection fraction &gt; 45%&#xD;
&#xD;
        For 1L AML population:&#xD;
&#xD;
          -  For Part 1 or Part 2 Expansion Cohorts 1 or 2: subjects with de novo AML suitable for&#xD;
             induction treatment with cytarabine and anthracyclines as per investigator judgement&#xD;
&#xD;
          -  For Part 2 Expansion Cohort 2: documented presence of FLT3 mutation (ITD or TKD ) and&#xD;
             suitable for midostaurin treatment as per investigator judgement.&#xD;
&#xD;
          -  For Part 2 Expansion Cohort 3: Subjects with secondary AML (e.g. AML-MRC , secondary&#xD;
             to myelodysplasia/MDS or therapy-related AML). Prior use of hypomethylating agents or&#xD;
             other therapies with curative intent for treatment previous hematological malignancies&#xD;
             or therapy-related AML is allowed. Subjects suitable for induction treatment with&#xD;
             liposomal cytarabine/daunorubicin as per investigator judgement.&#xD;
&#xD;
        For R/R AML population:&#xD;
&#xD;
          -  All Parts: Diagnosis of relapsed or refractory AML and suitable for treatment with&#xD;
             IDAC as per investigator judgement.&#xD;
&#xD;
          -  For Part 3 only: willingness and suitability to participate in DDI Cohort 1 or 2.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior exposure to MDM2 and MDM4 inhibitor (e.g. idasanutlin)&#xD;
&#xD;
          -  Known symptomatic CNS leukemia not controlled by adequate therapy.&#xD;
&#xD;
          -  Isolated extramedullary leukemia&#xD;
&#xD;
          -  Subjects with prior malignancy (some exceptions apply)&#xD;
&#xD;
          -  QTcF &gt; 470 ms at screening&#xD;
&#xD;
          -  Subjects who require treatment with moderate or strong CYP3A4 inducers within 14 days&#xD;
             prior to starting study treatment or during the study&#xD;
&#xD;
          -  Subjects who require use of herbal preparations/medications and dietary supplements&#xD;
             within 7 days prior to first dose and during the study&#xD;
&#xD;
          -  Subjects who require treatment with substrates of CYP3A4/5 with narrow therapeutic&#xD;
             index (within 24 hours prior to during and 48 hours after HDM201 administration)&#xD;
&#xD;
          -  Subjects who require treatment with moderate or strong CYP3A4 inhibitors within 48&#xD;
             hours prior to, during and 48 hours post HDM201 administration. (except for Part 3 DDI&#xD;
             Cohort 1 and 2)&#xD;
&#xD;
          -  Subject is pregnant or breastfeeding&#xD;
&#xD;
          -  WOCBP unless using highly effective methods of contraception during study treatment&#xD;
             and for an appropriate time period after last study treatment&#xD;
&#xD;
          -  Sexually active males unless they use a condom during intercourse while taking study&#xD;
             drug and for an appropriate time period after last study treatment&#xD;
&#xD;
        For Part 1 only:&#xD;
&#xD;
        - Subjects with a known favorable risk AML subtype at screening or subjects with FLT3&#xD;
        mutation&#xD;
&#xD;
        For Part 3 only:&#xD;
&#xD;
          -  DDI Cohort 1: use of posaconazole (other than the planned dosing required by the&#xD;
             protocol) within 7 days prior to start of the DDI investigation and for the duration&#xD;
             of the DDI period&#xD;
&#xD;
          -  DDI Cohort 2: use of midazolam (other than the planned dosing required by the&#xD;
             protocol) within 2 days prior to start of the DDI investigation and for the duration&#xD;
             of the DDI period&#xD;
&#xD;
          -  DDI Cohort 1 and 2: subjects who have received, or are expected to receive moderate or&#xD;
             strong inhibitors of CYP3A4 within 7 days prior to start of the DDI investigation, for&#xD;
             the duration of the investigation, and 24 hours after last blood sample collection for&#xD;
             PK assessment&#xD;
&#xD;
        Other protocol-defined inclusion/exclusion may apply.&#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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <removed_countries>
    <country>Israel</country>
    <country>Italy</country>
  </removed_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>November 13, 2018</study_first_submitted>
  <study_first_submitted_qc>November 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <last_update_submitted>January 6, 2020</last_update_submitted>
  <last_update_submitted_qc>January 6, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HDM201</keyword>
  <keyword>midostaurin</keyword>
  <keyword>cytarabine</keyword>
  <keyword>daunorubicin</keyword>
  <keyword>idarubicin</keyword>
  <keyword>liposomal cytarabine/daunorubicin</keyword>
  <keyword>acute myeloid leukemia (AML)</keyword>
  <keyword>1L newly diagnosed AML</keyword>
  <keyword>relapsed/refractory AML</keyword>
  <keyword>FLT3-mutation</keyword>
  <keyword>combination treatment</keyword>
  <keyword>dose escalation</keyword>
  <keyword>CR/CRi</keyword>
  <keyword>minimal residual disease</keyword>
  <keyword>DDI with CYP3A4 inhibitors</keyword>
  <keyword>DDI with sensitive CYP3A4 substrate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Posaconazole</mesh_term>
    <mesh_term>Daunorubicin</mesh_term>
    <mesh_term>Idarubicin</mesh_term>
    <mesh_term>Midostaurin</mesh_term>
    <mesh_term>Midazolam</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.</ipd_description>
  </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/NCT03760445
org study id: CHDM201A2101
secondary id: 2018-003107-19
nct id: NCT03760445
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a multi-center open-label Phase I/II study investigating orally administered HDM201
      in combination with chemotherapy in two populations: subjects with first line AML or subjects
      with relapsed/refractory AML. This study is conducted in three parts: dose escalation, dose
      expansion and DDI study.
This is a Phase 1 / 2 study. No patients were screened / enrolled. There are no data
      collected. There will be no CSR.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: 3 parts - two different populations Part 1 - escalation - parallel dose escalation in 1L AML subjects and in R/R subjects (up to 8 dose cohorts per arm.
Part 2 - expansion - parallel expansion in 3 cohorts of 1L AML, and 1 cohort of R/R AML after recommended dose of expansion was determined.
Part 3 - DDI - parallel enrollment or R/R AML subjects into 2 DDI Cohorts (one with CYP3A4 inhibitor, one with CYP3A4 substrate).
primary purpose: Treatment
masking: None (Open Label)
measure: Part 1 - Incidence of dose limiting toxicity (DLT)
time frame: first day of study treatment to 3 months after start of study treatment
description: number of DLTs by dose regimen of first line (1L) acute myeloid leukemia (AML) subjects during induction treatment; number of DLTs by dose regimen of relapsed/refractory (R/R) AML subjects during treatment
measure: Part 1 - Time to DLT
time frame: first day of study treatment to 3 months after start of study treatment
description: time from first dose to onset of DLT by dose regimen of 1L AML and R/R AML subjects
measure: Part 1 - Incidence and severity of Adverse Events (AEs)
time frame: first day of study treatment to 3 months after start of study treatment
description: number and grade of AEs by dose regimen of 1L AML and R/R AML subjects during DLT observation period
measure: Part 2 - Incidence and severity of AEs/serious adverse events (SAEs)
time frame: first day of study treatment until 8.5 months after start of study treatment
description: number and grade of AEs/SAEs by expansion cohort
measure: Part 2 - Percentage of participants with complete remission (CR)/CR with incomplete recovery (CRi) with adequate blood count recovery (ABCR)
time frame: first day of study treatment until 4.5 months after start of study treatment
description: Percentage of participants with CR/CRi with ABCR at the end of induction treatment for Expansion Cohort 1, and at the end of treatment for Expansion Cohort 4
measure: Part 2 - Incidence and severity of abnormal laboratory values
time frame: first day of study treatment until 8.5 months after start of study treatment
description: number and grade of abnormal laboratory results by expansion cohort
measure: Part 2 - Incidence and severity of abnormal electrocardiogram (ECG) results
time frame: first day of study treatment until 8.5 months after start of study treatment
description: number and severity of abnormal ECG results by expansion cohort
measure: Part 2 - Incidence and severity of abnormal vital signs
time frame: first day of study treatment until 8.5 months after start of study treatment
description: number and severity of abnormal vital signs by expansion cohort
measure: Part 3 - DDI Cohort 1 HDM201 Pharmacokinetics (PK) area under the curve (AUC)
time frame: first day of HDM201 dose to 10 days after start of HDM201
description: determine HDM201 AUC from time zero to the last measurable concentration sampling time (AUClast) in Cycle 1
measure: Part 3 - DDI Cohort 1 HDM201 PK maximum observed plasma concentration (Cmax)
time frame: first day of HDM201 dose to 10 days after start of HDM201
description: determine HDM201 Cmax in Cycle 1
measure: Part 3 - DDI Cohort 1 HDM201 PK average plasma concentration
time frame: first day of HDM201 dose to 10 days after start of HDM201
description: determine HDM201 average plasma concentration in Cycle 1
measure: Part 3 - DDI Cohort 1 HDM201 PK time of maximum observed plasma concentration (Tmax)
time frame: first day of HDM201 dose to 10 days after start of HDM201
description: determine HDM201 Tmax in Cycle 1
measure: Part 3 - DDI Cohort 2: midazolam PK AUC
time frame: first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)
description: determine midazolam AUC last and AUC from time zero to infinity (inf)
measure: Part 3 - DDI Cohort 2: midazolam PK Cmax
time frame: first dose of midazolam (Day-2) to 8 days after start of study treatment (HDM201)
description: determine midazolam Cmax
measure: Part 1 +2: HDM201 PK AUC
time frame: first day of study treatment to 7.5 months after start of study treatment
description: determine HDM201 AUC by dose regimen in Part 1, and Expansion Cohort in Part 2
measure: Part 1 +2: HDM201 PK Cmax
time frame: first day of study treatment to 7.5 months after start of study treatment
description: determine Cmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2
measure: Part 1 +2: HDM201 PK Tmax
time frame: first day of study treatment to 7.5 months after start of study treatment
description: determine Tmax of HDM201 by dose regimen in Part 2, and Expansion Cohort in Part 2
measure: Part 1 - incidence of AEs/SAEs
time frame: first day of study treatment to 8.5 months after start of study treatment
description: number and grade of AEs/SAEs, by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days
measure: Part 2 - all Expansion Cohorts: time to platelet recovery
time frame: first day of study treatment to 7.5 months after start of study treatment
description: determine time to platelet recovery by Expansion Cohort for each cycle
measure: Part 2 - all Expansion Cohorts: time to neutrophil recovery
time frame: first day of study treatment to 7.5 months after start of study treatment
description: determine time to neutrophil recovery by Expansion Cohort for each cycle
measure: Part 2 - all Expansion Cohorts: overall survival
time frame: first day of study treatment to 3 years after last patient is enrolled to Part 2
description: determine overall survival by Expansion Cohort
measure: Part 2 - all Expansion Cohorts: event-free survival
time frame: first day of study treatment to 3 years after last patient is enrolled to Part 2
description: determine event-free survival by Expansion Cohort
measure: Part 2 - all Expansion Cohorts: Percentage of subjects receiving Hematopoietic stem cell transplant (HSCT)
time frame: first day of study treatment to 3 years after last patient was enrolled to Part 2
description: percentage of subjects receiving HSCT after study treatment by Expansion Cohort.
measure: Part 2 - Expansion Cohorts 1 to 3: disease-free survival (DFS)
time frame: first day of study treatment to 3 years after last patient enrolled to Part 2
description: determine DFS by Expansion Cohort
measure: Part 2 - Expansion Cohorts 1 to 3: cumulative incidence of relapse (CIR)
time frame: first day of study treatment to 3 years after last patient enrolled to Part 2
description: determine CIR by Expansion Cohort
measure: Part 2 - Expansion Cohorts 2 and 3 - proportion of subjects with CR/CRi with ABCR
time frame: first day of study treatment to 7.5 months after start of study treatment
description: proportion of subjects achieving CR or CRi with ABCR by Expansion Cohort
measure: Part 2 - Expansion Cohorts 1 and 2: proportion of subjects with minimal/measurable residual disease (MRD) negativity
time frame: first day of study treatment to 7.5 months after start of study treatment
description: proportion of subjects achieving MRD negativity by Expansion Cohort
measure: Part 2 - expansion cohort 2: midostaurin PK AUC
time frame: first day of study treatment to 7.5 month after start of study treatment
description: determine midostaurin AUC
measure: Part 2 - expansion cohort 2: midostaurin PK Cmax
time frame: first day of study treatment to 7.5 month after start of study treatment
description: determine midostaurin Cmax during induction and consolidation treatment
measure: Part 2 - expansion cohort 2: midostaurin PK Tmax
time frame: first day of study treatment to 7.5 month after start of study treatment
description: determine midostaurin Tmax during induction and consolidation treatment
measure: Part 1 - incidence of abnormal laboratory values
time frame: first day of study treatment to 8.5 months after start of study treatment
description: number of abnormal laboratory results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days
measure: Part 1 - incidence of abnormal ECG results
time frame: first day of study treatment to 8.5 months after start of study treatment
description: number of abnormal ECG results by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days
measure: Part 1 - incidence of abnormal vital signs
time frame: first day of study treatment to 8.5 months after start of study treatment
description: number of abnormal vital signs by dose regimen for 1L AML and R/R AML subjects during study treatment + 30 days
arm group label: Part 1 - first line (1L) AML
arm group type: Experimental
description: 1L acute myeloid leukemia (AML) subjects receiving HDM201 in various doses/schedules in combination with cytarabine/anthracyclines
arm group label: Part 1 - relapsed/refractory (R/R) AML
arm group type: Experimental
description: R/R AML subjects receiving HDM201 in various doses/schedules in combination with cytarabine
arm group label: Part 2 - Expansion Cohort 1
arm group type: Experimental
description: 1L de novo AML subjects without documented FLT3 mutation receiving HDM201 at the recommended dose of expansion (RDE) in combination with cytarabine/anthracyclines
arm group label: Part 2 - Expansion Cohort 2
arm group type: Experimental
description: 1L de novo AML subjects with documented FLT3 mutation status receiving HDM201 at RDE in combination with cytarabine/anthracyclines and midostaurin
arm group label: Part 2 - Expansion Cohort 3
arm group type: Experimental
description: 1L secondary AML subjects receiving HDM201 at RDE in combination with liposomal cytarabine/daunorubicin
arm group label: Part 2 - Expansion Cohort 4
arm group type: Experimental
description: R/R AML subjects receiving HDM201 at RDE in combination with cytarabine
arm group label: Part 3 - DDI Cohort 1
arm group type: Experimental
description: R/R AML subjects receiving HDM201 at adjusted recommended Phase 3 dose (RP3D) determined in Part 2 in combination with cytarabine and posaconazole added in Cycle 1
arm group label: Part 3 - DDI Cohort 2
arm group type: Experimental
description: R/R AML subjects receiving HDM201 at RP3D in combination with cytarabine and midazolam
intervention type: Drug
intervention name: HDM201
description: 2.5 mg and 10mg capsules, given orally
arm group label: Part 1 - first line (1L) AML
arm group label: Part 1 - relapsed/refractory (R/R) AML
arm group label: Part 2 - Expansion Cohort 1
arm group label: Part 2 - Expansion Cohort 2
arm group label: Part 2 - Expansion Cohort 3
arm group label: Part 2 - Expansion Cohort 4
arm group label: Part 3 - DDI Cohort 1
arm group label: Part 3 - DDI Cohort 2
other name: none available
intervention type: Drug
intervention name: cytarabine
description: 20mg or 1000 mg or other strengths as locally available given intravenously
arm group label: Part 1 - first line (1L) AML
arm group label: Part 1 - relapsed/refractory (R/R) AML
arm group label: Part 2 - Expansion Cohort 1
arm group label: Part 2 - Expansion Cohort 2
arm group label: Part 2 - Expansion Cohort 3
arm group label: Part 2 - Expansion Cohort 4
arm group label: Part 3 - DDI Cohort 1
arm group label: Part 3 - DDI Cohort 2
other name: Ara-C, Cytosar
intervention type: Drug
intervention name: anthracycline
description: 20mg or other strength as locally available given intravenously
arm group label: Part 1 - first line (1L) AML
arm group label: Part 2 - Expansion Cohort 1
arm group label: Part 2 - Expansion Cohort 2
other name: daunorubicin or idarubicin, Rubidomycin or Idamycin
intervention type: Drug
intervention name: midostaurin
description: 25mg capsules given orally
arm group label: Part 2 - Expansion Cohort 2
other name: PKC412, Rydapt
intervention type: Drug
intervention name: liposomal cytarabine/daunorubicin
description: 100mg/44mg or other strength as locally available given intravenously
arm group label: Part 2 - Expansion Cohort 3
other name: Vyxeos
intervention type: Drug
intervention name: posaconazole
description: 100mg delayed release tablet or other strength as locally available given orally
arm group label: Part 3 - DDI Cohort 1
other name: Noxafil
intervention type: Drug
intervention name: midazolam
description: 2mg/mL oral solution or in other strength as locally available
arm group label: Part 3 - DDI Cohort 2
other name: midazolam HCl
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
country: Israel
country: Italy
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid, Acute
mesh term: Leukemia, Myeloid
mesh term: Cytarabine
mesh term: Posaconazole
mesh term: Daunorubicin
mesh term: Idarubicin
mesh term: Midostaurin
mesh term: Midazolam
sharing ipd: Undecided
ipd description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.