<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/NCT03247088</url>
  </required_header>
  <id_info>
    <org_study_id>2016-0592</org_study_id>
    <secondary_id>NCI-2018-01607</secondary_id>
    <secondary_id>2016-0592</secondary_id>
    <nct_id>NCT03247088</nct_id>
  </id_info>
  <brief_title>Sorafenib, Busulfan and Fludarabine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia Undergoing Donor Stem Cell Transplant</brief_title>
  <official_title>Phase I/II Study of Sorafenib Added to Busulfan and Fludarabine Conditioning Regimen in Patients With Relapsed/Refractory AML Undergoing Stem Cell Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>M.D. Anderson Cancer Center</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 phase I/II trial studies the best dose of sorafenib when given together with busulfan&#xD;
      and fludarabine in treating patients with acute myeloid leukemia that has come back or does&#xD;
      not respond to treatment and who are undergoing donor stem cell transplant. Sorafenib may&#xD;
      stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs&#xD;
      used in chemotherapy, such as busulfan and fludarabine, work in different ways to stop the&#xD;
      growth of cancer cells, either by killing the cells, by stopping them from dividing, or by&#xD;
      stopping them from spreading. Giving sorafenib with busulfan and fludarabine may work better&#xD;
      in treating patients with recurrent or refractory acute myeloid leukemia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To identify the maximum tolerated dose (MTD) of sorafenib when combined with busulfan and&#xD;
      fludarabine conditioning regimen.&#xD;
&#xD;
      II. To obtain preliminary evidence of efficacy.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine safety of this regimen as per National Cancer Institute (NCI) toxicity&#xD;
      criteria.&#xD;
&#xD;
      II. To determine time to neutrophil and platelet engraftment. III. To determine incidence of&#xD;
      acute and chronic graft versus host disease (GVHD).&#xD;
&#xD;
      IV. To determine relapse incidence. V. To determine non relapse mortality. VI. To determine&#xD;
      overall survival.&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. To study chemotherapy resistance. II. To study deoxyribonucleic acid (DNA) damage. III. To&#xD;
      study immune recovery and cytokines (both in plasma and cells).&#xD;
&#xD;
      OUTLINE: This is a phase I, dose escalation study of sorafenib, followed by a phase II study.&#xD;
&#xD;
      PRE-STEM CELL INFUSION: Patients receive sorafenib orally (PO) once daily (QD) or twice daily&#xD;
      (BID) on days -24 to -5, busulfan intravenously (IV) over 3 hours on days -20 and -13 and -6&#xD;
      and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression&#xD;
      or unacceptable toxicity.&#xD;
&#xD;
      STEM CELL INFUSION: Patients receive allogeneic hematopoietic stem cell transplant (HSCT) IV&#xD;
      in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4,&#xD;
      tacrolimus PO BID beginning day 5 for about 50 days, filgrastim subcutaneously (SC) on day 7&#xD;
      and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of&#xD;
      disease progression or unacceptable toxicity. Patients with matched unrelated donor receive&#xD;
      mycophenolate mofetil PO thrice daily (TID) or IV over 2 hours TID beginning on day 5 for up&#xD;
      to 90 days for longer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 30, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</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>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum tolerated dose (MTD) as defined by toxicity (Phase I)</measure>
    <time_frame>From day -24 pre-transplant to day 30 post-transplant</time_frame>
    <description>Toxicity is defined as grade 3 or higher regimen-related non-hematologic, non-infectious, and non-graft versus host disease (GVHD) toxicity occurring during the period from day -5 to pre-transplant to day 30 post-transplant. Dose-finding will be done using the Bayesian Model Averaging Continual Reassessment (BMA-CRM) method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression-free survival (PFS) (Phase II)</measure>
    <time_frame>Interval between day of transplant and day of death or disease progression, assessed up to 6 years</time_frame>
    <description>The method of Thall et al will be used to monitor PFS time. PFS will be estimated using the method of Kaplan and Meier. The relationship between patient prognostic covariates and PFS and overall survival (OS) time will be assessed by Bayesian survival time regression.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</measure>
    <time_frame>Up to 6 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS</measure>
    <time_frame>Interval between day of transplant and day of death, assessed up to 6 years</time_frame>
    <description>OS will be estimated using the method of Kaplan and Meier. Categorical variables will be tabulated. The relationship between patient prognostic covariates and PFS and OS time will be assessed by Bayesian survival time regression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-relapse mortality rate</measure>
    <time_frame>Up to 6 years</time_frame>
    <description>Defined as death from any cause other than relapse disease. These events will be tabulated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse rate</measure>
    <time_frame>Up to 6 years</time_frame>
    <description>These events will be tabulated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Graft failure</measure>
    <time_frame>Up to 6 years</time_frame>
    <description>These events will be tabulated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute and chronic graft versus host disease graded according to National Cancer Institute CTCAE version 4.0</measure>
    <time_frame>Up to 6 years</time_frame>
    <description>These events will be tabulated.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">74</enrollment>
  <condition>Recurrent Acute Myeloid Leukemia</condition>
  <condition>Refractory Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PRE-STEM CELL INFUSION: Patients receive sorafenib orally PO QD or BID on days -24 to -5, busulfan IV over 3 hours on days -20 and -13 and -6 and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity.&#xD;
STEM CELL INFUSION: Patients receive allogeneic HSCT IV in the absence of disease progression or unacceptable toxicity.&#xD;
POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus PO BID beginning day 5 for about 50 days, filgrastim SC on day 7 and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients with matched unrelated donor receive mycophenolate mofetil PO TID or IV over 2 hours TID beginning on day 5 for up to 90 days for longer.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Allogeneic Hematopoietic Stem Cell Transplantation</intervention_name>
    <description>Undergo allogeneic HSCT IV</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>Allogeneic</other_name>
    <other_name>Allogeneic Hematopoietic Cell Transplantation</other_name>
    <other_name>Allogeneic Stem Cell Transplantation</other_name>
    <other_name>HSC</other_name>
    <other_name>HSCT</other_name>
    <other_name>Stem Cell Transplantation, Allogeneic</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Busulfan</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>1, 4-Bis[methanesulfonoxy]butane</other_name>
    <other_name>BUS</other_name>
    <other_name>Bussulfam</other_name>
    <other_name>Busulfanum</other_name>
    <other_name>Busulfex</other_name>
    <other_name>Busulphan</other_name>
    <other_name>CB 2041</other_name>
    <other_name>CB-2041</other_name>
    <other_name>Glyzophrol</other_name>
    <other_name>GT 41</other_name>
    <other_name>GT-41</other_name>
    <other_name>Joacamine</other_name>
    <other_name>Methanesulfonic Acid Tetramethylene Ester</other_name>
    <other_name>Methanesulfonic acid, tetramethylene ester</other_name>
    <other_name>Mielucin</other_name>
    <other_name>Misulban</other_name>
    <other_name>Misulfan</other_name>
    <other_name>Mitosan</other_name>
    <other_name>Myeleukon</other_name>
    <other_name>Myeloleukon</other_name>
    <other_name>Myelosan</other_name>
    <other_name>Mylecytan</other_name>
    <other_name>Myleran</other_name>
    <other_name>Sulfabutin</other_name>
    <other_name>Tetramethylene Bis(methanesulfonate)</other_name>
    <other_name>Tetramethylene bis[methanesulfonate]</other_name>
    <other_name>WR-19508</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>(-)-Cyclophosphamide</other_name>
    <other_name>2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate</other_name>
    <other_name>Carloxan</other_name>
    <other_name>Ciclofosfamida</other_name>
    <other_name>Ciclofosfamide</other_name>
    <other_name>Cicloxal</other_name>
    <other_name>Clafen</other_name>
    <other_name>Claphene</other_name>
    <other_name>CP monohydrate</other_name>
    <other_name>CTX</other_name>
    <other_name>CYCLO-cell</other_name>
    <other_name>Cycloblastin</other_name>
    <other_name>Cycloblastine</other_name>
    <other_name>Cyclophospham</other_name>
    <other_name>Cyclophosphamid monohydrate</other_name>
    <other_name>Cyclophosphamide Monohydrate</other_name>
    <other_name>Cyclophosphamidum</other_name>
    <other_name>Cyclophosphan</other_name>
    <other_name>Cyclophosphane</other_name>
    <other_name>Cyclophosphanum</other_name>
    <other_name>Cyclostin</other_name>
    <other_name>Cyclostine</other_name>
    <other_name>Cytophosphan</other_name>
    <other_name>Cytophosphane</other_name>
    <other_name>Cytoxan</other_name>
    <other_name>Fosfaseron</other_name>
    <other_name>Genoxal</other_name>
    <other_name>Genuxal</other_name>
    <other_name>Ledoxina</other_name>
    <other_name>Mitoxan</other_name>
    <other_name>Neosar</other_name>
    <other_name>Revimmune</other_name>
    <other_name>Syklofosfamid</other_name>
    <other_name>WR- 138719</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Filgrastim</intervention_name>
    <description>Given SC</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>Filgrastim-aafi</other_name>
    <other_name>G-CSF</other_name>
    <other_name>Neupogen</other_name>
    <other_name>Nivestym</other_name>
    <other_name>r-metHuG-CSF</other_name>
    <other_name>Recombinant Methionyl Human Granulocyte Colony Stimulating Factor</other_name>
    <other_name>rG-CSF</other_name>
    <other_name>Tevagrastim</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>Fluradosa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mycophenolate Mofetil</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>CellCept</other_name>
    <other_name>MMF</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sorafenib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>BA4 43 9006</other_name>
    <other_name>BAY 43-9006</other_name>
    <other_name>Bay-439006</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (sorafenib, busulfan, fludarabine, HSCT)</arm_group_label>
    <other_name>FK 506</other_name>
    <other_name>Fujimycin</other_name>
    <other_name>Hecoria</other_name>
    <other_name>Prograf</other_name>
    <other_name>Protopic</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;= 18 and =&lt; 70 years&#xD;
&#xD;
          -  Patients with acute myeloid leukemia both flt3 positive and negative&#xD;
&#xD;
          -  Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor&#xD;
             available&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks (3 months)&#xD;
&#xD;
          -  Direct bilirubin =&lt; 1 mg/dL&#xD;
&#xD;
          -  Alanine transaminase (ALT) =&lt; 3 x upper limit of normal&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x the upper limit of normal&#xD;
&#xD;
          -  Creatinine clearance &gt;= 50&#xD;
&#xD;
          -  Diffusing capacity for carbon monoxide (DLCO) &gt; 50% of predicted corrected for&#xD;
             hemoglobin&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &gt;= 50%&#xD;
&#xD;
          -  Subjects must be able to understand and be willing to sign the written informed&#xD;
             consent form. A signed informed consent form must be appropriately obtained prior to&#xD;
             the conduct of any trial-specific procedure&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test performed&#xD;
             within 7 days prior to the start of study drug. Post-menopausal women (defined as no&#xD;
             menses for at least 1 year) and surgically sterilized women are not required to&#xD;
             undergo a pregnancy test&#xD;
&#xD;
          -  Subjects (men and women) of childbearing potential must agree to use adequate&#xD;
             contraception beginning at the signing of the informed consent form (ICF) until at&#xD;
             least 30 days after the last dose of study drug. The definition of adequate&#xD;
             contraception will be based on the judgment of the principal investigator or a&#xD;
             designated associate&#xD;
&#xD;
          -  Subject must be able to swallow and retain oral medication&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Acute myeloid leukemia in first complete molecular remission and favorable risk&#xD;
             disease as defined by presence of t(8:21) or inv (16)&#xD;
&#xD;
          -  Patients with a comorbidity score &gt; 3. The principal investigator is the final arbiter&#xD;
             of eligibility for comorbidity score &gt; 3&#xD;
&#xD;
          -  Uncontrolled hypertension (systolic pressure &gt; 140 mm Hg or diastolic pressure &gt; 90 mm&#xD;
             Hg [NCI-Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0] on&#xD;
             repeated measurement) despite optimal medical management&#xD;
&#xD;
          -  Active or clinically significant cardiac disease including:&#xD;
&#xD;
               -  Congestive heart failure - New York Heart Association (NYHA) &gt; class II&#xD;
&#xD;
               -  Active coronary artery disease&#xD;
&#xD;
               -  Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or&#xD;
                  digoxin&#xD;
&#xD;
               -  Unstable angina (anginal symptoms at rest), new-onset angina within 3 months&#xD;
                  before randomization, or myocardial infarction within 6 months before&#xD;
                  randomization&#xD;
&#xD;
          -  Evidence or history of bleeding diathesis or coagulopathy. Patients with bleeding due&#xD;
             to prior thrombocytopenia are permitted&#xD;
&#xD;
          -  Subject with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v. 4.0 grade 2 or&#xD;
             higher within 4 weeks before randomization; any other hemorrhage/bleeding event of&#xD;
             NCI-CTCAE v. 4.0 grade 3 or higher within 4 weeks before randomization&#xD;
&#xD;
          -  Subjects with thrombotic, embolic, venous, or arterial cerebrovascular event&#xD;
             (including transient ischemic attacks) within 6 months of informed consent&#xD;
&#xD;
          -  Subjects who have used strong CYP3A4 inducers (e.g., phenytoin, carbamazepine,&#xD;
             phenobarbital, St. John's wort [Hypericum perforatum], dexamethasone at a dose of&#xD;
             greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days&#xD;
             before randomization&#xD;
&#xD;
          -  Subjects with any previously untreated or concurrent cancer except cervical cancer&#xD;
             in-situ, treated basal cell carcinoma, or superficial bladder tumor. Subjects&#xD;
             surviving a cancer that was curatively treated and without evidence of disease for&#xD;
             more than 3 years before randomization are allowed. All cancer treatments must be&#xD;
             completed at least 3 years prior to study entry (i.e., signature date of the informed&#xD;
             consent form)&#xD;
&#xD;
          -  Presence of a non-healing wound, non-healing ulcer, or bone fracture&#xD;
&#xD;
          -  History of organ allograft (including corneal transplant)&#xD;
&#xD;
          -  Known or suspected allergy or hypersensitivity to any of the study drugs, study drug&#xD;
             classes, or excipients of the formulations given during the course of this trial&#xD;
&#xD;
          -  Any malabsorption condition&#xD;
&#xD;
          -  Women who are pregnant or breast-feeding&#xD;
&#xD;
          -  Inability to comply with the protocol and/or not willing or not available for&#xD;
             follow-up assessments&#xD;
&#xD;
          -  Any medical, psychological, or psychosocial condition which, in the investigator's&#xD;
             opinion, makes the subject unsuitable for trial participation&#xD;
&#xD;
          -  Major surgery within 30 days prior to start of study drug&#xD;
&#xD;
          -  Patients who received inotuzumab and/or gemtuzumab in the past&#xD;
&#xD;
          -  Therapeutic anticoagulation with vitamin-K antagonists (e.g., warfarin) or with&#xD;
             heparins and heparinoids&#xD;
&#xD;
               -  However, prophylactic anticoagulation as described below is allowed:&#xD;
&#xD;
                    -  Low dose warfarin (1 mg orally, once daily) with prothrombin time&#xD;
                       international normalized ratio (PT-INR). =&lt; 1.5 x upper limit of normal&#xD;
                       (ULN) is permitted. Infrequent bleeding or elevations in PT-INR have been&#xD;
                       reported in some subjects taking warfarin while on sorafenib or capecitabine&#xD;
                       therapy. Therefore, subjects taking concomitant warfarin should be monitored&#xD;
                       regularly for changes in PT, PT-INR or clinical bleeding episodes&#xD;
&#xD;
                    -  Low dose aspirin (=&lt; 100 mg daily)&#xD;
&#xD;
                    -  Prophylactic doses of heparin or low molecular weight heparin&#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>Uday R Popat</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Uday R. Popat</last_name>
      <phone>713-792-8750</phone>
      <email>upopat@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Uday R. Popat</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>MD Anderson Cancer Center Website</description>
  </link>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 8, 2017</study_first_submitted>
  <study_first_submitted_qc>August 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2017</study_first_posted>
  <last_update_submitted>August 17, 2023</last_update_submitted>
  <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 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</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Busulfan</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Sorafenib</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
    <mesh_term>Lenograstim</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/NCT03247088
org study id: 2016-0592
secondary id: NCI-2018-01607
secondary id: 2016-0592
nct id: NCT03247088
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase I/II trial studies the best dose of sorafenib when given together with busulfan
      and fludarabine in treating patients with acute myeloid leukemia that has come back or does
      not respond to treatment and who are undergoing donor stem cell transplant. Sorafenib may
      stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs
      used in chemotherapy, such as busulfan and fludarabine, work in different ways to stop the
      growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
      stopping them from spreading. Giving sorafenib with busulfan and fludarabine may work better
      in treating patients with recurrent or refractory acute myeloid leukemia.
PRIMARY OBJECTIVES:

      I. To identify the maximum tolerated dose (MTD) of sorafenib when combined with busulfan and
      fludarabine conditioning regimen.

      II. To obtain preliminary evidence of efficacy.

      SECONDARY OBJECTIVES:

      I. To determine safety of this regimen as per National Cancer Institute (NCI) toxicity
      criteria.

      II. To determine time to neutrophil and platelet engraftment. III. To determine incidence of
      acute and chronic graft versus host disease (GVHD).

      IV. To determine relapse incidence. V. To determine non relapse mortality. VI. To determine
      overall survival.

      TERTIARY OBJECTIVES:

      I. To study chemotherapy resistance. II. To study deoxyribonucleic acid (DNA) damage. III. To
      study immune recovery and cytokines (both in plasma and cells).

      OUTLINE: This is a phase I, dose escalation study of sorafenib, followed by a phase II study.

      PRE-STEM CELL INFUSION: Patients receive sorafenib orally (PO) once daily (QD) or twice daily
      (BID) on days -24 to -5, busulfan intravenously (IV) over 3 hours on days -20 and -13 and -6
      and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression
      or unacceptable toxicity.

      STEM CELL INFUSION: Patients receive allogeneic hematopoietic stem cell transplant (HSCT) IV
      in the absence of disease progression or unacceptable toxicity.

      POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4,
      tacrolimus PO BID beginning day 5 for about 50 days, filgrastim subcutaneously (SC) on day 7
      and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of
      disease progression or unacceptable toxicity. Patients with matched unrelated donor receive
      mycophenolate mofetil PO thrice daily (TID) or IV over 2 hours TID beginning on day 5 for up
      to 90 days for longer.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD) as defined by toxicity (Phase I)
time frame: From day -24 pre-transplant to day 30 post-transplant
description: Toxicity is defined as grade 3 or higher regimen-related non-hematologic, non-infectious, and non-graft versus host disease (GVHD) toxicity occurring during the period from day -5 to pre-transplant to day 30 post-transplant. Dose-finding will be done using the Bayesian Model Averaging Continual Reassessment (BMA-CRM) method.
measure: Progression-free survival (PFS) (Phase II)
time frame: Interval between day of transplant and day of death or disease progression, assessed up to 6 years
description: The method of Thall et al will be used to monitor PFS time. PFS will be estimated using the method of Kaplan and Meier. The relationship between patient prognostic covariates and PFS and overall survival (OS) time will be assessed by Bayesian survival time regression.
measure: Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to 6 years
measure: OS
time frame: Interval between day of transplant and day of death, assessed up to 6 years
description: OS will be estimated using the method of Kaplan and Meier. Categorical variables will be tabulated. The relationship between patient prognostic covariates and PFS and OS time will be assessed by Bayesian survival time regression.
measure: Non-relapse mortality rate
time frame: Up to 6 years
description: Defined as death from any cause other than relapse disease. These events will be tabulated.
measure: Relapse rate
time frame: Up to 6 years
description: These events will be tabulated.
measure: Graft failure
time frame: Up to 6 years
description: These events will be tabulated.
measure: Incidence of acute and chronic graft versus host disease graded according to National Cancer Institute CTCAE version 4.0
time frame: Up to 6 years
description: These events will be tabulated.
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
arm group type: Experimental
description: PRE-STEM CELL INFUSION: Patients receive sorafenib orally PO QD or BID on days -24 to -5, busulfan IV over 3 hours on days -20 and -13 and -6 and -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity.
STEM CELL INFUSION: Patients receive allogeneic HSCT IV in the absence of disease progression or unacceptable toxicity.
POST-STEM CELL INFUSION: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus PO BID beginning day 5 for about 50 days, filgrastim SC on day 7 and sorafenib PO BID beginning between days +30 and +120 for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients with matched unrelated donor receive mycophenolate mofetil PO TID or IV over 2 hours TID beginning on day 5 for up to 90 days for longer.
intervention type: Procedure
intervention name: Allogeneic Hematopoietic Stem Cell Transplantation
description: Undergo allogeneic HSCT IV
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: Allogeneic
other name: Allogeneic Hematopoietic Cell Transplantation
other name: Allogeneic Stem Cell Transplantation
other name: HSC
other name: HSCT
other name: Stem Cell Transplantation, Allogeneic
intervention type: Drug
intervention name: Busulfan
description: Given IV
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: 1, 4-Bis[methanesulfonoxy]butane
other name: BUS
other name: Bussulfam
other name: Busulfanum
other name: Busulfex
other name: Busulphan
other name: CB 2041
other name: CB-2041
other name: Glyzophrol
other name: GT 41
other name: GT-41
other name: Joacamine
other name: Methanesulfonic Acid Tetramethylene Ester
other name: Methanesulfonic acid, tetramethylene ester
other name: Mielucin
other name: Misulban
other name: Misulfan
other name: Mitosan
other name: Myeleukon
other name: Myeloleukon
other name: Myelosan
other name: Mylecytan
other name: Myleran
other name: Sulfabutin
other name: Tetramethylene Bis(methanesulfonate)
other name: Tetramethylene bis[methanesulfonate]
other name: WR-19508
intervention type: Drug
intervention name: Cyclophosphamide
description: Given IV
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: (-)-Cyclophosphamide
other name: 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
other name: Carloxan
other name: Ciclofosfamida
other name: Ciclofosfamide
other name: Cicloxal
other name: Clafen
other name: Claphene
other name: CP monohydrate
other name: CTX
other name: CYCLO-cell
other name: Cycloblastin
other name: Cycloblastine
other name: Cyclophospham
other name: Cyclophosphamid monohydrate
other name: Cyclophosphamide Monohydrate
other name: Cyclophosphamidum
other name: Cyclophosphan
other name: Cyclophosphane
other name: Cyclophosphanum
other name: Cyclostin
other name: Cyclostine
other name: Cytophosphan
other name: Cytophosphane
other name: Cytoxan
other name: Fosfaseron
other name: Genoxal
other name: Genuxal
other name: Ledoxina
other name: Mitoxan
other name: Neosar
other name: Revimmune
other name: Syklofosfamid
other name: WR- 138719
intervention type: Biological
intervention name: Filgrastim
description: Given SC
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: Filgrastim-aafi
other name: G-CSF
other name: Neupogen
other name: Nivestym
other name: r-metHuG-CSF
other name: Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
other name: rG-CSF
other name: Tevagrastim
intervention type: Drug
intervention name: Fludarabine
description: Given IV
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: Fluradosa
intervention type: Drug
intervention name: Mycophenolate Mofetil
description: Given PO
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: CellCept
other name: MMF
intervention type: Drug
intervention name: Sorafenib
description: Given PO
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: BA4 43 9006
other name: BAY 43-9006
other name: Bay-439006
intervention type: Drug
intervention name: Tacrolimus
description: Given PO
arm group label: Treatment (sorafenib, busulfan, fludarabine, HSCT)
other name: FK 506
other name: Fujimycin
other name: Hecoria
other name: Prograf
other name: Protopic
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Uday R Popat
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.mdanderson.org
description: MD Anderson Cancer Center Website
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Mycophenolic Acid
mesh term: Cyclophosphamide
mesh term: Busulfan
mesh term: Fludarabine
mesh term: Sorafenib
mesh term: Tacrolimus
mesh term: Lenograstim