xml: <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/NCT06022003</url>
    </required_header>
    <id_info>
      <org_study_id>FILOAML-RR-01 OGILAR</org_study_id>
      <secondary_id>2022-501372-25-00</secondary_id>
      <nct_id>NCT06022003</nct_id>
    </id_info>
    <brief_title>Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects ≥18 Years of Age With Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia</brief_title>
    <acronym>OGILAR</acronym>
    <official_title>Open-label, Phase 2 Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects ≥18 Years of Age With Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>French Innovative Leukemia Organisation</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Acute Leukemia French Association</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>French Innovative Leukemia Organisation</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>
        Approximately 30% of adult AML subjects are refractory to induction therapy. Furthermore, of&#xD;
        those who achieve CR, approximately 75% will relapse. FLT3-mutated AML comprise an especially&#xD;
        poor prognosis group.&#xD;
  &#xD;
        Until now, there was no established standard for relapsed subjects with FLT3 mutations and&#xD;
        less than 20% will achieve CR with subsequent treatment.&#xD;
  &#xD;
        In phase 3 Study ADMIRAL Trial, gilteritinib has resulted in CRc in over 25% of subjects&#xD;
        receiving 120 mg/day before on study HSCT. With this treatment, the median overall survival&#xD;
        is at 9.3 months, furthermore, gilteritinib was well tolerated at the proposed doses. This&#xD;
        study has been designed for R/R patients for which gilteritinib as single agent has been&#xD;
        showed to be superior to high- and low-intensity chemotherapy (Perl, NEJM 2019, Supp Table&#xD;
        S4) and patients included in this study will receive this treatment. Beyond high- or&#xD;
        low-intensity chemotherapy, other options available are best supportive car or other clinical&#xD;
        trials.&#xD;
  &#xD;
        The aim of this study is to assess the efficacy and safety of the addition of&#xD;
        oral-azacitidine to salvage treatment by gilteritinib in subjects ≥18 years of age with&#xD;
        relapsed/refractory FLT3-mutated acute myeloid leukemia&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        AML is characterized by the clonal expansion of myeloid blasts in the BM, peripheral blood&#xD;
        and extramedullary tissues which disrupts normal hematopoiesis. It is a heterogeneous&#xD;
        disease, encompassing a large number of distinctly subtypes that may have different clinical&#xD;
        presentations and responses to treatment. AML is defined by the WHO as a myeloid neoplasm&#xD;
        with 20% or more blasts in the peripheral blood or BM.&#xD;
  &#xD;
        Internal tandem duplication (ITD) in the FLT3 gene is one of the most frequent mutations&#xD;
        found in AML. FLT3-ITD is associated with poor prognosis and has emerged as a relevant&#xD;
        therapeutic target. FLT3-ITD is usually conserved at relapse, suggesting that FLT3-ITD&#xD;
        AML-initiating cells are key targets for long-lasting remission. FLT3-TKI, developed as&#xD;
        ATP-competitive inhibitors, are currently the focus of new development strategies in&#xD;
        FLT3-mutated AML, particularly in combination with intensive or non-intensive chemotherapies&#xD;
        in newly diagnosed (ND) FLT3 mutated AML or in R/R situation. Type I inhibitors, including&#xD;
        midostaurin, gilteritinib, and crenolanib, have activity against FLT3-ITD and tyrosine kinase&#xD;
        domain (TKD) mutations. Type II inhibitors, including sorafenib and quizartinib, do not have&#xD;
        activity against FLT3-TKD mutations. Although first-generation FLT3 inhibitors, such as&#xD;
        midostaurin 10 and sorafenib 11, have marginal single-agent activity in active disease, they&#xD;
        have shown promising activity as maintenance therapies, notably after HSCT for sorafenib 14.&#xD;
        Conversely, several FLT3-TKI, such as quizartinib, crenolanib, and gilteritinib, have&#xD;
        single-agent activity that lead to complete or near-complete remission, providing a strong&#xD;
        rationale to combine these agents with other chemotherapies.&#xD;
  &#xD;
        The ADMIRAL phase 3 trial, also designed for R/R FLT3-mutated AML patients, recently&#xD;
        demonstrated the superiority of gilteritinib as single agent over the control treatment arm,&#xD;
        which was determined by investigators prior to 2:1 randomization between mitoxantrone,&#xD;
        etoposide, cytarabine; fludarabine, cytarabine, granulocyte colony-stimulating factor,&#xD;
        idarubicin; AZA or LDAC. These regimens are recognized as acceptable salvage strategies in&#xD;
        this situation, although other combinations based on intermediate- or high-dose cytarabine or&#xD;
        even single-agent cytarabine are also widely used. In the ADMIRAL trial, OS was significantly&#xD;
        improved in the gilteritinib arm compared to the control arm with HR at 0.64 (95%CI:&#xD;
        0.49-0.83; p &lt; 0.001). The median OS was 9.3 months in the gilteritinib arm and 5.6 months in&#xD;
        the control arm. The CR and CRi rates were 21.1% and 25.5% in the gilteritinib arm vs. 10.5%&#xD;
        and 4.8% in the standard arm 2. Gilteritinib was generally well tolerated but was associated&#xD;
        with increased incidence of GI side effects, most frequently diarrhea although nausea has&#xD;
        been occasionally observed. Increase in bilirubin and transaminase can be seen with&#xD;
        gilteritinib but are usually self-resolving and transient. Posterior reversible&#xD;
        encephalopathy and pancreatitis are rare (&lt;1-2%) but important side effects to be aware of.&#xD;
        These results led to the approval of gilteritinib monotherapy in the US and Europe in&#xD;
        patients with R/R FLT3 mutated AML and it is now the gold standard treatment in such&#xD;
        situation. However, long lasting remission with gilteritinib as single agent are uncommon&#xD;
        since various resistance mechanisms allow AML to escape. Innovative strategies have to be&#xD;
        established in order to improve these results. In that setting, associations with ICT, HMA,&#xD;
        other targeted therapies are currently developed.&#xD;
  &#xD;
        AZA was first investigated as a cytotoxic agent in the 1960s and 1970s in R/R AML and a dose-&#xD;
        and time-dependent effect of AZA was evident, with higher remission rates and reduced&#xD;
        toxicity reported in patients who received lower doses or continuous infusion schedule of AZA&#xD;
  &#xD;
        QUAZAR trial used an oral formulation of AZA (oral-AZA) that is not bioequivalent to&#xD;
        injectable AZA, as maintenance therapy in patients with AML who were in CR/CRi after ICT 22.&#xD;
        Median OS from randomization was significantly longer with oral-AZA than with placebo (24.7&#xD;
        months vs. 14.8 months, respectively; p&lt;0.001). Median RFS was also significantly longer with&#xD;
        oral-AZA than with placebo (10.2 months vs. 4.8 months, respectively; p&lt;0.001). The most&#xD;
        common AE in both groups were grade 1 or 2 GI events. Common grade 3 or 4 AE were neutropenia&#xD;
        (in 41% of patients in the oral-AZA group and 24% of patients in the placebo group) and&#xD;
        thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was&#xD;
        preserved during oral-AZA treatment. Among those who were MRD+ at baseline, patients in the&#xD;
        oral-AZA arm had a higher rate of conversion to MRD- status vs. placebo: 37% versus 19%,&#xD;
        respectively. These data suggest an effective anti-leukemic therapy and not only an ability&#xD;
        to maintain a stable situation, among these MRD responders, 9 of 38 (24%) patients in the&#xD;
        oral-AZA arm converted to MRD-negativity after &gt; 6 months on treatment, vs. only 1of 22 (5%)&#xD;
        patients in the placebo arm. Moreover, during the 63rd ASH annual meeting, Döhner et al.&#xD;
        confirmed that Oral-AZA, NPM1 and FLT3 mutational status, cytogenetic risk, as well as MRD&#xD;
        status at baseline were independent predictors of survival.&#xD;
  &#xD;
        In front line situation, LACEWING study was a phase 3, randomized study comparing&#xD;
        gilteritinib+AZA vs. AZA for ND FLT3-mutated AML in patients unfit for ICT. In this trial in&#xD;
        patients with ND FLT3 mutated AML unfit for ICT, gilteritinib+AZA led to significantly higher&#xD;
        CRc rates but similar OS vs. AZA alone. Based on these results, an independent data&#xD;
        monitoring committee recommended the study be terminated for futility, citing that the&#xD;
        results are unlikely to demonstrate a statistically significant increase in OS. However&#xD;
        subsequent therapy after AZA failure, notably with other regimen including FLT3-TKI, could&#xD;
        have precluded transition of better CRc results to better OS results&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 30, 2023</start_date>
    <completion_date type="Anticipated">March 2026</completion_date>
    <primary_completion_date type="Anticipated">September 2025</primary_completion_date>
    <phase>Phase 2</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>characterize the rate of composite complete remission (CRc) as the best response to treatment during the first 3-months treatment</measure>
      <time_frame>from inclusion to 3 months treatment</time_frame>
      <description>the rate of composite complete remission (CRc) [defined by addition of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and complete remission with incomplete platelet recovery (CRp)]</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>characterize the Incidence and relatedness of adverse events (AE) and the percent of early death, with the combination of oral-azacitidine and gilteritinib</measure>
      <time_frame>from inclusion and during treatment administration (median estimated is 6 months treatment)</time_frame>
      <description>description of toxicities according CTCAE v4.0, and death</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>characterize the rate of CR, rate of CRi, rate of CRp, rate of CRh</measure>
      <time_frame>from inclusion to the first 6 months treatment</time_frame>
      <description>rate of complete remission (CR), rate of complete remission with incomplete hematologic recovery (CRi), rate of complete remission with incomplete platelet recovery (CRp), rate of complete remission with partial hematologic recovery (CRh)</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">33</enrollment>
    <condition>AML, Adult</condition>
    <condition>Refractory AML</condition>
    <condition>Relapsed Adult AML</condition>
    <condition>FLT3-TKD Mutation</condition>
    <condition>FLT3-ITD</condition>
    <arm_group>
      <arm_group_label>Gilteritinib + Azacitidine oral (CC-486)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Gilteritinib 120 mg/day, PO by 28 days-cycle&#xD;
  Azacitidine orale (CC-486) 300 mg/day, PO Day 1 to day 14, by 28 days-cycle</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>AzaCITIDine Oral Tablet</intervention_name>
      <description>AML study treatment</description>
      <arm_group_label>Gilteritinib + Azacitidine oral (CC-486)</arm_group_label>
      <other_name>Onureg</other_name>
      <other_name>CC-486</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Xospata</intervention_name>
      <description>R/R FLT3-mutated AML standard treatment</description>
      <arm_group_label>Gilteritinib + Azacitidine oral (CC-486)</arm_group_label>
      <other_name>Gilteritinib</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Confirmed diagnosis of acute myeloid leukemia (AML) according to world health&#xD;
               organization (WHO) 2016 classification&#xD;
  &#xD;
            2. Presence of FLT3-mutation(s) at inclusion: in case of FLT3-ITD, the ITD/wt ratio must&#xD;
               be &gt; 0.05 ; in case of FLT3-TKD, the mutation must be at D835 or I836 position with a&#xD;
               VAF &gt; 5% by NGS.&#xD;
  &#xD;
            3. Subjects must be primary refractory or relapsed (R/R) to 1st line intensive&#xD;
               chemotherapy (ICT) for AML. Hydroxyurea is allowed for the control of peripheral&#xD;
               leukemic blasts in patients with leukocytosis.&#xD;
  &#xD;
          3a. Primary refractory is defined as no CR or CRi after at least one course of ICT&#xD;
          (including &quot;7+3&quot;, gemtuzumab ozogamycin (GO)-based and CPX-351, including or not&#xD;
          midostaurine) or two courses (maximum 4) of AZA and venetoclax 3b. Relapse after 1st line&#xD;
          ICT for AML is defined as the first hematologic relapse with bone marrow blasts &gt;5% after&#xD;
          one line of treatment for AML that includes at least one course of ICT (one line of&#xD;
          treatment for AML can include induction, re-induction, consolidation, allogeneic HSCT and&#xD;
          maintenance) 3c. Relapse after 1st line non intensive chemotherapy for AML is defined as&#xD;
          the first hematologic relapse with bone marrow blasts &gt;5% after or during treatment by AZA&#xD;
          venetoclax regardless of number of cycles 4. 1st line intensive treatment may or may not&#xD;
          include previous treatment by tyrosine kinase inhibitor (TKI) except gilteritinib.&#xD;
  &#xD;
          5. Patients who never received oral azacitidine 6. Age ≥ 18 years 7. Adequate baseline&#xD;
          organ function defined by the criteria below:&#xD;
  &#xD;
            -  adequate renal function as demonstrated by a creatinine clearance ≥ 50 ml/min;&#xD;
               calculated by the Cockcroft gault formula or measured by 24-hours urine collection&#xD;
  &#xD;
            -  aspartate aminotransferase (AST) ≤ 2.5 × ULN&#xD;
  &#xD;
            -  alanine aminotransferase (ALT) ≤ 2.5× ULN&#xD;
  &#xD;
            -  bilirubin ≤ 1.5 × ULN&#xD;
  &#xD;
            -  adequate cardiac function with LVEF ≥45% 8. ECOG &lt; 3 (appendix 1) 9. Absence of any&#xD;
               psychological, familial, sociological, or geographical conditions potentially&#xD;
               hampering compliance with the study protocol and follow-up schedule 10. Patient is&#xD;
               suitable for oral administration of study drug. 11. A female subject is eligible to&#xD;
               participate if she is not pregnant and at least one of the following conditions&#xD;
               applies: 9a. Not a woman of childbearing potential (WOCBP) as defined in&#xD;
               post-menopausal (defined as at least 1 year without any menses) prior to Screening, or&#xD;
               documented as surgically sterile (at least 1 month prior to Screening) 9b. WOCBP&#xD;
               agrees to follow the contraceptive treatment starting at screening and continue&#xD;
               throughout the study period, and for at least 180 days after the final study drug&#xD;
               administration 12. Patient must be affiliated to the french social security (health&#xD;
               insurance) 13. Signed written informed consent for the study 14. Female subject must&#xD;
               agree not to breastfeed starting at screening and throughout the study period, and for&#xD;
               60 days after the final study drug administration.&#xD;
  &#xD;
               15. Female subject must not donate ova starting at screening and throughout the study&#xD;
               period, and for 180 days after the final study drug administration.&#xD;
  &#xD;
               16. A male subject with female partner(s) of childbearing potential must agree to use&#xD;
               contraception starting at screening and continue throughout the study period, for at&#xD;
               least 120 days after the final study drug administration.&#xD;
  &#xD;
               17. Male subject must not donate sperm starting at screening and throughout the study&#xD;
               period and for 120 days after the final study drug administration.&#xD;
  &#xD;
          Exclusion criteria&#xD;
  &#xD;
          1. Subjects with any of the following current or previous diagnoses:&#xD;
  &#xD;
          1a. AML secondary to prior myeloproliferative syndrome (MPN)&#xD;
  &#xD;
          1b. Acute promyelocytic leukemia (APL) and core binding factor (CBF) AML&#xD;
  &#xD;
          1c. DNA fragility or bone marrow (BM) failure syndromes&#xD;
  &#xD;
          1d. Blastic plasmacytoid dendritic cell neoplasm&#xD;
  &#xD;
          1e. Acute lymphoblastic leukemia including ambiguous lineage 2. Patients ≥ 3rd line of&#xD;
          treatment, HSCT being not considered as a line of treatment 3. Patients previously treated&#xD;
          by AZA as single agent for AML are not allowed 4. Subjects that have previously been&#xD;
          treated by gilteritinib 5. Subjects that have previously been treated by oral azacitidine&#xD;
          6. Clinically active central nervous system (CNS) leukemia 7. Subjects who have received&#xD;
          more than 1 prior allogeneic HSCT 8. Subjects who have relapsed within 100 days after&#xD;
          allogeneic HSCT 9. Presence of Grade 2 or above graft-versus-host disease (GVHD), including&#xD;
          acute, chronic, or overlap; or escalation of therapy for GVHD within 14 days prior to&#xD;
          randomization 10. Subject requires treatment with concomitant drugs that are strong&#xD;
          inducers of cytochrome P450 (CYP)3A (Annexe 7) 11. Subject requires treatment with&#xD;
          concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of&#xD;
          drugs that are considered absolutely essential for the care of the subject (Annexe 7) 12.&#xD;
          Severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis&#xD;
          or hyperbilirubinemia) 13. Participant has clinically significant abnormality of&#xD;
          coagulation profile, such as disseminated intravascular coagulation (DIC).&#xD;
  &#xD;
          14. Subject exhibiting evidence of other clinically significant uncontrolled systemic&#xD;
          infection requiring therapy (viral, bacterial, or fungal).&#xD;
  &#xD;
          15. Isolated extramedullary leukemia relapse 16. History of another malignancy within the&#xD;
          past 3 years except basal cell carcinoma of the skin or cervix in situ carcinoma 17. Any&#xD;
          other serious medical condition, laboratory abnormalities or psychiatric illness that would&#xD;
          place the participant at an unacceptable risk or prevent them from giving informed consent&#xD;
          18. Severe medical or mental condition precluding the administration of protocol treatments&#xD;
          19. persons deprived of their liberty by judicial or administrative decision, persons&#xD;
          subject to a legal protection measure (guardianship, curatorship, legal protection),&#xD;
          persons under psychiatric care 20. Other comorbidity that the physician judges to be&#xD;
          incompatible with conventional intensive chemotherapy which must be reviewed and approved&#xD;
          by the study medical monitor before study enrolment 21. Subject with Positive HIV test (due&#xD;
          to potential drug-drug interactions). HIV testing will be performed at screening, if&#xD;
          required per local guidelines or institutional standards. Subject known to be positive for&#xD;
          hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier&#xD;
          status with undetectable PCR viral load on antivirals (non-exclusionary medications) are&#xD;
          not excluded 22. Known hypersensitivity to the study medication 23. Subject has congestive&#xD;
          heart failure classified as New York Heart Association Class III and IV unless a screening&#xD;
          echocardiogram performed within 3 months prior to study entry results in a left ventricular&#xD;
          ejection fraction that is ≥ 45% 24. Subject with mean Fridericia-corrected QT interval&#xD;
          (QTcF) &gt; 450 ms at screening based on central reading 25. Subject with a history of Long QT&#xD;
          Syndrome at screening&#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_contact>
      <last_name>Pierre-Yves DUMAS, MD, PhD</last_name>
      <phone>+ 33 5 57 65 65 11</phone>
      <email>pierre-yves.dumas@u-bordeaux.fr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Ariane MINEUR</last_name>
      <phone>+ 33 5 57 62 31 08</phone>
      <email>ariane.mineur@chu-bordeaux.fr</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Amiens CHU</name>
        <address>
          <city>Amiens</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Angers CHU</name>
        <address>
          <city>Angers</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Hôpital d'Instruction des Armées PERCY</name>
        <address>
          <city>Clamart</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>CHU Estaing</name>
        <address>
          <city>Clermont-Ferrand</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Créteil CHU HENRI MONDOR</name>
        <address>
          <city>Créteil</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Grenoble CHU</name>
        <address>
          <city>Grenoble</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>CHU Lille</name>
        <address>
          <city>Lille</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Limoges CHU</name>
        <address>
          <city>Limoges</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Lyon sud CHU</name>
        <address>
          <city>Lyon</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Marseille IPC</name>
        <address>
          <city>Marseille</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Nantes CHU</name>
        <address>
          <city>Nantes</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Centre Antoine Lacassagne</name>
        <address>
          <city>Nice</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Paris Saint Louis</name>
        <address>
          <city>Paris</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Bordeaux CHU</name>
        <address>
          <city>Pessac</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Rennes CHU</name>
        <address>
          <city>Rennes</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Centre de Lutte Contre le Cancer H. Becquerel</name>
        <address>
          <city>Rouen</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>ICANS - Institut de cancérologie de strasbourg europe</name>
        <address>
          <city>Strasbourg</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Toulouse - IUCT Oncopole - Service d'Hématologie</name>
        <address>
          <city>Toulouse</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Nancy CHU</name>
        <address>
          <city>vandoeuvre les Nancy</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Versailles CH</name>
        <address>
          <city>Versailles</city>
          <country>France</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 28, 2023</study_first_submitted>
    <study_first_submitted_qc>August 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 1, 2023</study_first_posted>
    <last_update_submitted>September 1, 2023</last_update_submitted>
    <last_update_submitted_qc>September 1, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 6, 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>Leukemia, Myeloid, Acute</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Azacitidine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06022003
  org study id: FILOAML-RR-01 OGILAR
  secondary id: 2022-501372-25-00
  nct id: NCT06022003
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Approximately 30% of adult AML subjects are refractory to induction therapy. Furthermore, of
        those who achieve CR, approximately 75% will relapse. FLT3-mutated AML comprise an especially
        poor prognosis group.
  
        Until now, there was no established standard for relapsed subjects with FLT3 mutations and
        less than 20% will achieve CR with subsequent treatment.
  
        In phase 3 Study ADMIRAL Trial, gilteritinib has resulted in CRc in over 25% of subjects
        receiving 120 mg/day before on study HSCT. With this treatment, the median overall survival
        is at 9.3 months, furthermore, gilteritinib was well tolerated at the proposed doses. This
        study has been designed for R/R patients for which gilteritinib as single agent has been
        showed to be superior to high- and low-intensity chemotherapy (Perl, NEJM 2019, Supp Table
        S4) and patients included in this study will receive this treatment. Beyond high- or
        low-intensity chemotherapy, other options available are best supportive car or other clinical
        trials.
  
        The aim of this study is to assess the efficacy and safety of the addition of
        oral-azacitidine to salvage treatment by gilteritinib in subjects ≥18 years of age with
        relapsed/refractory FLT3-mutated acute myeloid leukemia
  AML is characterized by the clonal expansion of myeloid blasts in the BM, peripheral blood
        and extramedullary tissues which disrupts normal hematopoiesis. It is a heterogeneous
        disease, encompassing a large number of distinctly subtypes that may have different clinical
        presentations and responses to treatment. AML is defined by the WHO as a myeloid neoplasm
        with 20% or more blasts in the peripheral blood or BM.
  
        Internal tandem duplication (ITD) in the FLT3 gene is one of the most frequent mutations
        found in AML. FLT3-ITD is associated with poor prognosis and has emerged as a relevant
        therapeutic target. FLT3-ITD is usually conserved at relapse, suggesting that FLT3-ITD
        AML-initiating cells are key targets for long-lasting remission. FLT3-TKI, developed as
        ATP-competitive inhibitors, are currently the focus of new development strategies in
        FLT3-mutated AML, particularly in combination with intensive or non-intensive chemotherapies
        in newly diagnosed (ND) FLT3 mutated AML or in R/R situation. Type I inhibitors, including
        midostaurin, gilteritinib, and crenolanib, have activity against FLT3-ITD and tyrosine kinase
        domain (TKD) mutations. Type II inhibitors, including sorafenib and quizartinib, do not have
        activity against FLT3-TKD mutations. Although first-generation FLT3 inhibitors, such as
        midostaurin 10 and sorafenib 11, have marginal single-agent activity in active disease, they
        have shown promising activity as maintenance therapies, notably after HSCT for sorafenib 14.
        Conversely, several FLT3-TKI, such as quizartinib, crenolanib, and gilteritinib, have
        single-agent activity that lead to complete or near-complete remission, providing a strong
        rationale to combine these agents with other chemotherapies.
  
        The ADMIRAL phase 3 trial, also designed for R/R FLT3-mutated AML patients, recently
        demonstrated the superiority of gilteritinib as single agent over the control treatment arm,
        which was determined by investigators prior to 2:1 randomization between mitoxantrone,
        etoposide, cytarabine; fludarabine, cytarabine, granulocyte colony-stimulating factor,
        idarubicin; AZA or LDAC. These regimens are recognized as acceptable salvage strategies in
        this situation, although other combinations based on intermediate- or high-dose cytarabine or
        even single-agent cytarabine are also widely used. In the ADMIRAL trial, OS was significantly
        improved in the gilteritinib arm compared to the control arm with HR at 0.64 (95%CI:
        0.49-0.83; p < 0.001). The median OS was 9.3 months in the gilteritinib arm and 5.6 months in
        the control arm. The CR and CRi rates were 21.1% and 25.5% in the gilteritinib arm vs. 10.5%
        and 4.8% in the standard arm 2. Gilteritinib was generally well tolerated but was associated
        with increased incidence of GI side effects, most frequently diarrhea although nausea has
        been occasionally observed. Increase in bilirubin and transaminase can be seen with
        gilteritinib but are usually self-resolving and transient. Posterior reversible
        encephalopathy and pancreatitis are rare (<1-2%) but important side effects to be aware of.
        These results led to the approval of gilteritinib monotherapy in the US and Europe in
        patients with R/R FLT3 mutated AML and it is now the gold standard treatment in such
        situation. However, long lasting remission with gilteritinib as single agent are uncommon
        since various resistance mechanisms allow AML to escape. Innovative strategies have to be
        established in order to improve these results. In that setting, associations with ICT, HMA,
        other targeted therapies are currently developed.
  
        AZA was first investigated as a cytotoxic agent in the 1960s and 1970s in R/R AML and a dose-
        and time-dependent effect of AZA was evident, with higher remission rates and reduced
        toxicity reported in patients who received lower doses or continuous infusion schedule of AZA
  
        QUAZAR trial used an oral formulation of AZA (oral-AZA) that is not bioequivalent to
        injectable AZA, as maintenance therapy in patients with AML who were in CR/CRi after ICT 22.
        Median OS from randomization was significantly longer with oral-AZA than with placebo (24.7
        months vs. 14.8 months, respectively; p<0.001). Median RFS was also significantly longer with
        oral-AZA than with placebo (10.2 months vs. 4.8 months, respectively; p<0.001). The most
        common AE in both groups were grade 1 or 2 GI events. Common grade 3 or 4 AE were neutropenia
        (in 41% of patients in the oral-AZA group and 24% of patients in the placebo group) and
        thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was
        preserved during oral-AZA treatment. Among those who were MRD+ at baseline, patients in the
        oral-AZA arm had a higher rate of conversion to MRD- status vs. placebo: 37% versus 19%,
        respectively. These data suggest an effective anti-leukemic therapy and not only an ability
        to maintain a stable situation, among these MRD responders, 9 of 38 (24%) patients in the
        oral-AZA arm converted to MRD-negativity after > 6 months on treatment, vs. only 1of 22 (5%)
        patients in the placebo arm. Moreover, during the 63rd ASH annual meeting, Döhner et al.
        confirmed that Oral-AZA, NPM1 and FLT3 mutational status, cytogenetic risk, as well as MRD
        status at baseline were independent predictors of survival.
  
        In front line situation, LACEWING study was a phase 3, randomized study comparing
        gilteritinib+AZA vs. AZA for ND FLT3-mutated AML in patients unfit for ICT. In this trial in
        patients with ND FLT3 mutated AML unfit for ICT, gilteritinib+AZA led to significantly higher
        CRc rates but similar OS vs. AZA alone. Based on these results, an independent data
        monitoring committee recommended the study be terminated for futility, citing that the
        results are unlikely to demonstrate a statistically significant increase in OS. However
        subsequent therapy after AZA failure, notably with other regimen including FLT3-TKI, could
        have precluded transition of better CRc results to better OS results
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: characterize the rate of composite complete remission (CRc) as the best response to treatment during the first 3-months treatment
  time frame: from inclusion to 3 months treatment
  description: the rate of composite complete remission (CRc) [defined by addition of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and complete remission with incomplete platelet recovery (CRp)]
  measure: characterize the Incidence and relatedness of adverse events (AE) and the percent of early death, with the combination of oral-azacitidine and gilteritinib
  time frame: from inclusion and during treatment administration (median estimated is 6 months treatment)
  description: description of toxicities according CTCAE v4.0, and death
  measure: characterize the rate of CR, rate of CRi, rate of CRp, rate of CRh
  time frame: from inclusion to the first 6 months treatment
  description: rate of complete remission (CR), rate of complete remission with incomplete hematologic recovery (CRi), rate of complete remission with incomplete platelet recovery (CRp), rate of complete remission with partial hematologic recovery (CRh)
  arm group label: Gilteritinib + Azacitidine oral (CC-486)
  arm group type: Experimental
  description: Gilteritinib 120 mg/day, PO by 28 days-cycle
  Azacitidine orale (CC-486) 300 mg/day, PO Day 1 to day 14, by 28 days-cycle
  intervention type: Drug
  intervention name: AzaCITIDine Oral Tablet
  description: AML study treatment
  arm group label: Gilteritinib + Azacitidine oral (CC-486)
  other name: Onureg
  other name: CC-486
  intervention type: Drug
  intervention name: Xospata
  description: R/R FLT3-mutated AML standard treatment
  arm group label: Gilteritinib + Azacitidine oral (CC-486)
  other name: Gilteritinib
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Pierre-Yves DUMAS, MD, PhD
  phone: + 33 5 57 65 65 11
  email: pierre-yves.dumas@u-bordeaux.fr
  last name: Ariane MINEUR
  phone: + 33 5 57 62 31 08
  email: ariane.mineur@chu-bordeaux.fr
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  country: France
  responsible party type: Sponsor
  mesh term: Leukemia, Myeloid, Acute
  mesh term: Azacitidine
  sharing ipd: No