<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/NCT03235973</url>
  </required_header>
  <id_info>
    <org_study_id>CEREAL-IPC 2016-010</org_study_id>
    <nct_id>NCT03235973</nct_id>
  </id_info>
  <brief_title>Cladribine Dose Escalation in Conditioning Regimen Prior to Allo-HSCT for Refractory Acute Leukemia and Myelodysplastic Syndromes</brief_title>
  <acronym>CEREAL</acronym>
  <official_title>Cladribine Dose Escalation in Conditioning Regimen Prior to Allo-HSCT for Refractory Acute Leukemia and Myelodysplastic Syndromes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Paoli-Calmettes</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut Paoli-Calmettes</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators focused on patients with refractory acute leukemia or MDS and designed a&#xD;
      phase 1 trial of escalated cladribine doses in the Cla-Flu-Bu RTC regimen using PK-guided&#xD;
      myeloablative busulfan doses. This scheme allows combining different optimization of RTC&#xD;
      experienced over years (Flu-Bu RTC, PK-guided myeloablative busulfan doses, a second purine&#xD;
      analog cladribine) to approach a specific platform to treat refractory diseases.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 28, 2018</start_date>
  <completion_date type="Anticipated">April 2021</completion_date>
  <primary_completion_date type="Anticipated">April 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>estimation of the maximal tolerable dose,if any,and recommended phase II dose of cladribine administered as in combination with fludarabine and PK-guided IV busulfan prior Allo-HSCT for refractory acute leukemia and myelodysplastic syndrome (MDS)</measure>
    <time_frame>30 days after Allo-HSCT</time_frame>
    <description>Occurrence ratio of dose-limiting toxicity defined as any grade ≥ 3 toxicity according to CTCAE (version 4.03 ) attributable to conditioning regimen (extra-medullary toxicity), considered to be related or probably related to the Cla-Fu-Bu RTC by the investigator.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of acute Graft versus host disease</measure>
    <time_frame>100 days</time_frame>
    <description>Cumulative incidence of acute Graft versus host disease according to Gluckberg's classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of chronic Graft versus host disease</measure>
    <time_frame>1 year</time_frame>
    <description>Cumulative incidence of chronic Graft versus host disease according to NIH classification</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of relapse</measure>
    <time_frame>1 year</time_frame>
    <description>Cumulative incidence of relapse at 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of Non Relapse Mortality</measure>
    <time_frame>100 days, 1 year</time_frame>
    <description>Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">29</enrollment>
  <condition>Leukemia, Myeloid, Acute</condition>
  <condition>Leukemia, Lymphoblastic, Acute</condition>
  <arm_group>
    <arm_group_label>Fludarabine-Cladribine-Busulfan conditioning regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine-Cladribine-Busulfan conditioning regimen</intervention_name>
    <description>Conditioning regimen will be performed from day -6 to day -2 and contains:&#xD;
Fludarabine 10 mg/m²/d during 5 days (day-6 to day-2).&#xD;
Cladribine during 5 days (day-6 to day-2) at one the following define dose level:&#xD;
Dose 1: 10 mg/m²/d&#xD;
Dose 2: 15 mg/m²/d&#xD;
Dose 3: 20 mg/m²/d&#xD;
Dose 4: 25 mg/m²/d&#xD;
IV busulfan will be given on day-6 using fixed dose as following:&#xD;
If age ≤ 60 years: starting dose of 130 mg/m²&#xD;
If age &gt; 60 years: starting dose of 100 mg/m² No busulfan will be administered at day-5, allowing the pharmacokinetic (PK) analyses . Subsequent infusion of IV busulfan will be performed from day-4 to day-2 at the dose recommended by PK analyses</description>
    <arm_group_label>Fludarabine-Cladribine-Busulfan conditioning regimen</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-70&#xD;
&#xD;
          -  ECOG 0 or 1&#xD;
&#xD;
          -  Acute leukemia (AML or ALL) without criteria for CR or high risk MDS without criteria&#xD;
             for CR&#xD;
&#xD;
          -  Availability of a donor among following oHLA identical sibling oHaploidentical donor&#xD;
             o10/10 or 9/10 allele-level HLA matched unrelated donor&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
          -  Patient affiliated to the national &quot;Social Security&quot; regimen or beneficiary of this&#xD;
             regimen&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication for Allo-HSCT&#xD;
&#xD;
          -  Cord blood Allo-HSCT&#xD;
&#xD;
          -  Current active disease or positive serology for HIV, and/or HCV with detectable&#xD;
             viremia and/ or HBV with positive Hbs Antigen.&#xD;
&#xD;
          -  Renal failure with creatinine clearance &lt; 30 ml/ min&#xD;
&#xD;
          -  Decompensated haemolytic anaemia&#xD;
&#xD;
          -  Hypersensitivity to an active substance or to any of the excipients&#xD;
&#xD;
          -  Acute urinary infection&#xD;
&#xD;
          -  Pre-existing haemorrhagic cystitis&#xD;
&#xD;
          -  Woman of childbearing potential not using an effective contraception .&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Any serious concurrent uncontrolled medical disorder&#xD;
&#xD;
          -  Any psychological, familial, sociological or geographical condition potentially&#xD;
             hampering compliance with the study protocol and follow-up schedule.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raynier Devillier, MD,PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Paoli-Calmettes</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dominique Genre, MD</last_name>
    <phone>+33491223778</phone>
    <email>drci.up@ipc.unicancer.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jihane Pakradouni, PharmD, PhD</last_name>
    <phone>+33491223778</phone>
    <email>drci.up@ipc.unicancer.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Institut Paoli-Calmettes</name>
      <address>
        <city>Marseille</city>
        <state>Bouches-du-Rhône</state>
        <zip>13009</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dominique Genre, MD</last_name>
      <phone>+33491223778</phone>
      <email>drci.up@ipc.unicancer.fr</email>
    </contact>
    <investigator>
      <last_name>Raynier Devillier, MD,PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>June 26, 2018</last_update_submitted>
  <last_update_submitted_qc>June 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>refractory acute leukemia</keyword>
  <keyword>refractory myelodysplastic syndrome</keyword>
  <keyword>cladribine dose escalation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Busulfan</mesh_term>
    <mesh_term>Cladribine</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/NCT03235973
org study id: CEREAL-IPC 2016-010
nct id: NCT03235973
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The investigators focused on patients with refractory acute leukemia or MDS and designed a
      phase 1 trial of escalated cladribine doses in the Cla-Flu-Bu RTC regimen using PK-guided
      myeloablative busulfan doses. This scheme allows combining different optimization of RTC
      experienced over years (Flu-Bu RTC, PK-guided myeloablative busulfan doses, a second purine
      analog cladribine) to approach a specific platform to treat refractory diseases.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: estimation of the maximal tolerable dose,if any,and recommended phase II dose of cladribine administered as in combination with fludarabine and PK-guided IV busulfan prior Allo-HSCT for refractory acute leukemia and myelodysplastic syndrome (MDS)
time frame: 30 days after Allo-HSCT
description: Occurrence ratio of dose-limiting toxicity defined as any grade ≥ 3 toxicity according to CTCAE (version 4.03 ) attributable to conditioning regimen (extra-medullary toxicity), considered to be related or probably related to the Cla-Fu-Bu RTC by the investigator.
measure: Cumulative incidence of acute Graft versus host disease
time frame: 100 days
description: Cumulative incidence of acute Graft versus host disease according to Gluckberg's classification
measure: Cumulative incidence of chronic Graft versus host disease
time frame: 1 year
description: Cumulative incidence of chronic Graft versus host disease according to NIH classification
measure: Cumulative incidence of relapse
time frame: 1 year
description: Cumulative incidence of relapse at 1 year
measure: Cumulative incidence of Non Relapse Mortality
time frame: 100 days, 1 year
description: Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT
arm group label: Fludarabine-Cladribine-Busulfan conditioning regimen
arm group type: Experimental
intervention type: Drug
intervention name: Fludarabine-Cladribine-Busulfan conditioning regimen
description: Conditioning regimen will be performed from day -6 to day -2 and contains:
Fludarabine 10 mg/m²/d during 5 days (day-6 to day-2).
Cladribine during 5 days (day-6 to day-2) at one the following define dose level:
Dose 1: 10 mg/m²/d
Dose 2: 15 mg/m²/d
Dose 3: 20 mg/m²/d
Dose 4: 25 mg/m²/d
IV busulfan will be given on day-6 using fixed dose as following:
If age ≤ 60 years: starting dose of 130 mg/m²
If age > 60 years: starting dose of 100 mg/m² No busulfan will be administered at day-5, allowing the pharmacokinetic (PK) analyses . Subsequent infusion of IV busulfan will be performed from day-4 to day-2 at the dose recommended by PK analyses
arm group label: Fludarabine-Cladribine-Busulfan conditioning regimen
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Raynier Devillier, MD,PhD
role: Principal Investigator
affiliation: Institut Paoli-Calmettes
last name: Dominique Genre, MD
phone: +33491223778
email: drci.up@ipc.unicancer.fr
last name: Jihane Pakradouni, PharmD, PhD
phone: +33491223778
email: drci.up@ipc.unicancer.fr
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Preleukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Myelodysplastic Syndromes
mesh term: Fludarabine
mesh term: Busulfan
mesh term: Cladribine