<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/NCT03805932</url>
  </required_header>
  <id_info>
    <org_study_id>190042</org_study_id>
    <secondary_id>19-C-0042</secondary_id>
    <nct_id>NCT03805932</nct_id>
  </id_info>
  <brief_title>Moxetumomab Pasudotox-tdfk (Lumoxiti(TM)) and Either Rituximab (Rituxan(R)) or Ruxience for Relapsed Hairy Cell Leukemia</brief_title>
  <official_title>A Phase I Study of Moxetumomab Pasudotox-tdfk (Lumoxiti (TM)) and Either Rituximab (Rituxan (R)) or Ruxience for Relapsed Hairy Cell Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Hairy cell leukemia (HCL) is a rare, slow-growing blood cancer in which the bone marrow makes&#xD;
      too many of certain white blood cells. The antibody Rituximab/Ruxience binds to a protein in&#xD;
      cancerous white blood cells and is often used to treat HCL. Researchers want to see if&#xD;
      combining it with the drug Moxetumomab pasudotox-tdfk (also called Lumoxiti) can fight HCL&#xD;
      better.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To test the safety of Moxetumomab pasudotox taken with Rituximab/Ruxience for people with HCL&#xD;
      or HCL variant.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People age 18 years and older with HCL or HCL variant that has not responded to standard&#xD;
      therapy&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Blood, heart, and urine tests&#xD;
&#xD;
      Test of blood oxygen levels&#xD;
&#xD;
      Review of bone marrow. This can be from previous test results or a new sample.&#xD;
&#xD;
      Scans&#xD;
&#xD;
      Exercise test&#xD;
&#xD;
      Participants will get the study drugs in up to 8 cycles. A cycle will last about 28 days.&#xD;
&#xD;
      The study drugs will be given through a plastic tube in a vein.&#xD;
&#xD;
      In the first week of cycle 1, participants will have:&#xD;
&#xD;
      1 visit to get Rituximab or Ruxience for 7.5 hours&#xD;
&#xD;
      3 visits to get Lumoxiti for 30 minutes per infusion&#xD;
&#xD;
      In the first week of cycles 2-8, participants will have:&#xD;
&#xD;
        1. visit to get Rituximab/Ruxience for 2-4 hours and Lumoxiti for 30 minutes&#xD;
&#xD;
        2. visits to get Lumoxiti for 30 minutes per infusion&#xD;
&#xD;
      Participants will be asked to drink lots of water and take aspirin during the cycles. They&#xD;
      will get drugs to minimize allergic reactions.&#xD;
&#xD;
      Participants will repeat screening tests at visits throughout the cycles and 1 follow-up&#xD;
      visit. They may have an eye exam.&#xD;
&#xD;
      ...&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all&#xD;
           leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL&#xD;
           variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the&#xD;
           relapsed/refractory population due to its poor prognosis and response to standard purine&#xD;
           analog chemotherapy. HCLv cells are CD25-negative and wild type for BRAF, so HCLv&#xD;
           patients are not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that&#xD;
           express unmutated IGHV4-34 are wild-type for BRAF, remain brightly CD22 positive, and&#xD;
           confer a poor prognosis when treated with chemotherapy.&#xD;
&#xD;
        -  Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain&#xD;
           (Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin,&#xD;
           which kills CD22+ cells by binding to CD22 via the Fv fragment, and induction of&#xD;
           apoptotic cell death catalytic inhibition of protein synthesis in the cytosol.&#xD;
&#xD;
        -  Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR)&#xD;
           rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with&#xD;
           reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis.&#xD;
&#xD;
        -  Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting&#xD;
           its CR endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4&#xD;
           2.5%), and HUS (grade 3-4 6.3%), both reversible.&#xD;
&#xD;
        -  Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for HCL&#xD;
           which can consistently eradicate minimal residual disease (MRD), and this is associated&#xD;
           with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has&#xD;
           accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the&#xD;
           treatment of adult patients with HCL.&#xD;
&#xD;
        -  Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to&#xD;
           the bacterial-based toxin, and/or had collections of HCL cells not completely eradicated&#xD;
           by Moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-CD20&#xD;
           monoclonal antibody (Mab) rituximab or Ruxience to Moxetumomab pasudotox-tdfk.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      -To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab/Ruxience&#xD;
      used at the planned dose level, in patients with HCL and HCLv.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with &gt;=2-years 1&#xD;
           month response, at least 1 other therapy.&#xD;
&#xD;
        -  Need for treatment, either 1) ANC &lt;1/nL, 2) Hgb &lt;10g/dL, 3) Plt &lt;100/nL, 4) symptomatic&#xD;
           splenomegaly, or enlarging HCL mass &gt; 2cm in short axis&#xD;
&#xD;
        -  Serum creatinine &lt; 1.5 mg/dL, or creatinine clearance greater than or equal to 60 mL/min&#xD;
           by Cockcroft-Gault equation, where creatinine clearance = (140-age)(kg weight)/(72 x&#xD;
           Creatinine).&#xD;
&#xD;
        -  No uncontrolled infection or cardiopulmonary dysfunction&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Phase I trial, two arm, non-randomized, dose escalation&#xD;
&#xD;
        -  Administration:&#xD;
&#xD;
             -  Patients 1-13: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30&#xD;
                min, Rituximab 375 mg/m^2 iv, 50-400 mg/hr.&#xD;
&#xD;
             -  Patients 14-26: Moxetumomab pasudotox-tdfk 40 mcg/kg intravenous (iv) over 30 min,&#xD;
                Ruxience 375 mg/m2 iv, 50-400 mg/hr&#xD;
&#xD;
             -  Rituximab or Ruxience day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk&#xD;
                days 1, 3, and 5.&#xD;
&#xD;
             -  Patients will receive up 4 cycles past documentation of CR without MRD, maximum 8.&#xD;
&#xD;
             -  To prevent renal toxicity and hypovolemia, patients will be encouraged to drink&#xD;
                water gradually, approximately 0.5-1 cup/hour or 6L/day, not going &gt;3 hours without&#xD;
                drinking from days 1 to 8 and to keep a hydration diary to record daily fluid&#xD;
                consumption.&#xD;
&#xD;
             -  To prevent rituximab/Ruxience toxicity, patients will receive prophylactic&#xD;
                dexamethasone orally 0.5- 2 hours before the 1st dose of rituximab, and before&#xD;
                subsequent doses until rituximab/Ruxience infusion reactions are not seen. Patients&#xD;
                will also receive diphenhydramine, famotidine, and acetaminophen.&#xD;
&#xD;
             -  Dexamethasone 4 mg orally (maximum 2 doses/day) will be given as needed to treat&#xD;
                nausea or fever associated with Moxetumomab pasudotox-tdfk, which might prevent&#xD;
                adequate water intake&#xD;
&#xD;
        -  Statistical design:&#xD;
&#xD;
             -  Up to 26 patients are intended to be treated in the trial. While a total of 26&#xD;
                evaluable patients will be enrolled, the accrual ceiling will be set at 30 to&#xD;
                include screen failures and inevaluable patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 3, 2019</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Actual">July 7, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>safety and toxicity</measure>
    <time_frame>4 weeks</time_frame>
    <description>Determine recommended safe dose of moxetumomab pasudotox-tdfk and rituximab/Ruxience.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rates</measure>
    <time_frame>1, 2 and 3.5 years after EOT, then every 2 years</time_frame>
    <description>Percentage of patients whose cancer shrinks or disappears after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRD-free rates</measure>
    <time_frame>1, 2 and 3.5 years after EOT, then every 2 years</time_frame>
    <description>Percentage of patients without minimal residual disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response duration</measure>
    <time_frame>1, 2 and 3.5 years after EOT, then every 2 years</time_frame>
    <description>Time of initial response until documented tumor progression</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Hairy Cell Leukemia</condition>
  <arm_group>
    <arm_group_label>1 - Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Moxetumomab Pasudotox-tdfk + Rituximab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2- Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Moxetumomab Pasudotox-tdfk + Ruxience</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Moxetumomab Pasudotox-tdfk</intervention_name>
    <description>Moxetumomab pasudotox-tdfk is administered at 30-40 ug/Kg iv over 30 min given on days 1, 3, 5 of each cycle.</description>
    <arm_group_label>1 - Dose Escalation</arm_group_label>
    <arm_group_label>2- Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab will be administered at 375mg/m^2 iv, 50-400 mg/hr. On cycle 1, Rituximab is given on day -2, on subsequent cycles, Rituximab is given on day 1.</description>
    <arm_group_label>1 - Dose Escalation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Ruxience</intervention_name>
    <description>Ruxience will be administered at 375mg/m^2 iv, 50-400 mg/hr. On cycle 1, Ruxience is given on day -2, on subsequent cycles, Ruxience is given on day 1 (Delta)</description>
    <arm_group_label>2- Dose Expansion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Diagnosis of HCL or HCLv.&#xD;
&#xD;
          -  Treatment required for either 1) Absolute neutrophil count (ANC) &lt;1/nL, 2) Hemoglobin&#xD;
             &lt;10g/dL, 3) Platelets&lt;100/nL, 4) symptomatic splenomegaly, or 5) enlarging HCL mass &gt;&#xD;
             2cm in short axis. Patients who have eligible blood counts within 4 weeks from the&#xD;
             initiation of study will not be considered ineligible if subsequent blood counts prior&#xD;
             to enrollment fluctuate and become ineligible up until the time of enrollment.&#xD;
&#xD;
          -  Patients must be Pseudomonas-immunotoxin naive.&#xD;
&#xD;
          -  HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with &gt;=2-years&#xD;
             1 month response, at least 1 other therapy. Age greater than or equal to 18 years as&#xD;
             the disease under study, HCL/HCLv, has not been reported in children &lt; age 18.&#xD;
&#xD;
          -  ECOG performance status less than or equal to2 (Karnofsky greater than or equal to&#xD;
             60%)&#xD;
&#xD;
          -  Patients must have adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Total bilirubin less than or equal to 1.5 mg/dL, unless consistent with Gilbert s&#xD;
                  (ratio between total and direct bilirubin &gt; 5)&#xD;
&#xD;
               -  AST and ALT less than or equal to 3x upper limit of normal (ULN)&#xD;
&#xD;
               -  Alkaline phosphatase &lt; 2.5 ULN&#xD;
&#xD;
               -  Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater&#xD;
                  than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine&#xD;
                  clearance = (140-age)(Kg weight)/(72 x Creatinine)&#xD;
&#xD;
               -  Serum albumin greater than or equal to 2 g/dL&#xD;
&#xD;
               -  Partial thromboplastin time (PTT) or Prothrombin time (PT)/International&#xD;
                  Normalized Ratio &lt; 2.5x ULN (If on warfarin, PT/INR &lt; 3.5x ULN; If on any other&#xD;
                  anticoagulation, Prothrombin time (PT) &lt; 2.5x baseline)&#xD;
&#xD;
               -  Fibrinogen greater than or equal to 0.5 lower limit of normal&#xD;
&#xD;
          -  The effects of moxetumomab pasudotox-tdfk and rituximab/Ruxience on the developing&#xD;
             human fetus are unknown therefore participants must use effective methods of&#xD;
             contraception as directed below.&#xD;
&#xD;
               -  Females of childbearing potential (&lt; 50 years) who are sexually active with a&#xD;
                  non-sterilized male partner must use a highly effective method of contraception&#xD;
                  prior to study entry and or the duration of study participation and must agree to&#xD;
                  continue using such precautions for 12 months after completion of&#xD;
                  rituximab/Ruxience administration. Contraception after this point should be&#xD;
                  discussed with a responsible physician. Periodic abstinence, the rhythm method,&#xD;
                  and the withdrawal method are not acceptable methods of contraception. Females of&#xD;
                  childbearing potential are defined as those who are not surgically sterile (i.e.,&#xD;
                  bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or&#xD;
                  those who are premenarchal or postmenopausal (defined as 12 months with no menses&#xD;
                  without an alternative medical cause). A highly effective method of contraception&#xD;
                  is defined as one that results in a low failure rate (i.e., less than 1% per&#xD;
                  year) when used consistently and correctly. Not all methods of contraception are&#xD;
                  highly effective. Should a woman become pregnant or suspect she is pregnant while&#xD;
                  she or her partner is participating in this study, she should inform her treating&#xD;
                  physician immediately.&#xD;
&#xD;
               -  Non-sterilized males who are sexually active with a female partner of&#xD;
                  childbearing potential must use an effective method of contraception from Day 1&#xD;
                  until 90 days after receipt of the final dose of investigational product. It is&#xD;
                  required that a female partner of a male subject also use an effective method of&#xD;
                  contraception throughout this period.&#xD;
&#xD;
          -  Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
          -  Patients must be willing to co-enroll in the investigator s companion protocol&#xD;
             10C-0066 titled Collection of Human Samples to Study Hairy Cell and other Leukemias,&#xD;
             and to Develop Recombinant Immunotoxins for Cancer Treatment.&#xD;
&#xD;
        EXCLUSION CRITIERIA:&#xD;
&#xD;
          -  Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks or&#xD;
             treatment with rituximab/Ruxience within last 3 months prior to initiation of&#xD;
             treatment.&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents.&#xD;
&#xD;
          -  Breastfeeding within the projected duration of the study, starting with the screening&#xD;
             visit through 6 months after the last dose of rituximab/Ruxience. Pregnant women are&#xD;
             excluded from this study because moxetumomab pasudotox-tdfk and rituximab/Ruxience are&#xD;
             agents with the potential for teratogenic or abortifacient effects. Because there is&#xD;
             an unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with moxetumomab pasudotox-tdfk and rituximab/Ruxience,&#xD;
             breastfeeding should be discontinued if the mother is treated with moxetumomab&#xD;
             pasudotox-tdfk and rituximab/Ruxience.&#xD;
&#xD;
          -  Patients with known brain metastases should be excluded from this clinical trial&#xD;
             because of their poor prognosis and because they often develop progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other adverse events.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, uncontrolled hypertension, uncontrolled pulmonary infection, pulmonary&#xD;
             edema or psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          -  Patients with retinal or choroidal detachment.&#xD;
&#xD;
          -  Positive for Hepatitis B core antibody or surface antigen unless the patient is on&#xD;
             Tenofovir or Entecavir and Hepatitis B Viral deoxyribonucleic acid (DNA) load is &lt;2000&#xD;
             IU/mL&#xD;
&#xD;
          -  Active second malignancy requiring treatment other than minor resection of indolent&#xD;
             cancers like basal cell and squamous skin cancers.&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients unless taking appropriate&#xD;
             anti-HIV medications with a CD4 count of &gt; 200. Otherwise, there may be an increased&#xD;
             risk of lethal infections when temporarily suppressing normal B-cells.&#xD;
&#xD;
          -  History of an allogeneic bone marrow transplant.&#xD;
&#xD;
          -  Patients with a history of both thromboembolism and known congenital hypercoagulable&#xD;
             conditions.&#xD;
&#xD;
          -  Radioimmunotherapy within 2 years prior to enrollment in the study.&#xD;
&#xD;
          -  Patients with history of thrombotic microangiopathy or thrombotic microangiopathy&#xD;
             /HUS.&#xD;
&#xD;
          -  Patients with corrected QT interval (Frederica) elevation &gt; 500 msec (manually&#xD;
             over-read by medically qualified person) based on at least two separate 12-lead ECGs.&#xD;
&#xD;
          -  Patients on high dose estrogen (defined as &gt; 0.625 mg/day of an estrogen compound).&#xD;
&#xD;
          -  Oxygen saturation at rest &lt; 88% measured by pulse oximetry or PaO2 less than or equal&#xD;
             to 55 mm Hg.&#xD;
&#xD;
          -  Patients with life expectancy of less than 6 months.&#xD;
&#xD;
          -  Patients with clinical evidence of disseminated intravascular coagulation (Grade 3-4).&#xD;
&#xD;
          -  Patients with &lt; 50% of predicted forced expiratory volume (FEV1) or &lt; 50% of predicted&#xD;
             diffusing capacity for carbon monoxide, corrected for hemoglobin concentration and&#xD;
             alveolar volume (DLCO). Note: Patients with no prior history of pulmonary illness are&#xD;
             not required to have pulmonary function testing (PFT). Forced expiratory volume will&#xD;
             be assessed after bronchodilator therapy.&#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>Robert J Kreitman, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-C-0042.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>July 11, 2023</verification_date>
  <study_first_submitted>January 15, 2019</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 16, 2019</study_first_posted>
  <last_update_submitted>July 12, 2023</last_update_submitted>
  <last_update_submitted_qc>July 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HCL Variant</keyword>
  <keyword>Recombinant Immunotoxin</keyword>
  <keyword>Monoclonal Antibody</keyword>
  <keyword>Targeted Therapy</keyword>
  <keyword>Biologic Therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Hairy Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Immunotoxin HA22</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.All IPD recorded in the medical record will be shared with intramural investigators upon request.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data available during the study and indefinitely.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.</ipd_access_criteria>
  </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/NCT03805932
org study id: 190042
secondary id: 19-C-0042
nct id: NCT03805932
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Hairy cell leukemia (HCL) is a rare, slow-growing blood cancer in which the bone marrow makes
      too many of certain white blood cells. The antibody Rituximab/Ruxience binds to a protein in
      cancerous white blood cells and is often used to treat HCL. Researchers want to see if
      combining it with the drug Moxetumomab pasudotox-tdfk (also called Lumoxiti) can fight HCL
      better.

      Objective:

      To test the safety of Moxetumomab pasudotox taken with Rituximab/Ruxience for people with HCL
      or HCL variant.

      Eligibility:

      People age 18 years and older with HCL or HCL variant that has not responded to standard
      therapy

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Blood, heart, and urine tests

      Test of blood oxygen levels

      Review of bone marrow. This can be from previous test results or a new sample.

      Scans

      Exercise test

      Participants will get the study drugs in up to 8 cycles. A cycle will last about 28 days.

      The study drugs will be given through a plastic tube in a vein.

      In the first week of cycle 1, participants will have:

      1 visit to get Rituximab or Ruxience for 7.5 hours

      3 visits to get Lumoxiti for 30 minutes per infusion

      In the first week of cycles 2-8, participants will have:

        1. visit to get Rituximab/Ruxience for 2-4 hours and Lumoxiti for 30 minutes

        2. visits to get Lumoxiti for 30 minutes per infusion

      Participants will be asked to drink lots of water and take aspirin during the cycles. They
      will get drugs to minimize allergic reactions.

      Participants will repeat screening tests at visits throughout the cycles and 1 follow-up
      visit. They may have an eye exam.

      ...
Background:

        -  Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all
           leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL
           variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the
           relapsed/refractory population due to its poor prognosis and response to standard purine
           analog chemotherapy. HCLv cells are CD25-negative and wild type for BRAF, so HCLv
           patients are not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that
           express unmutated IGHV4-34 are wild-type for BRAF, remain brightly CD22 positive, and
           confer a poor prognosis when treated with chemotherapy.

        -  Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain
           (Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin,
           which kills CD22+ cells by binding to CD22 via the Fv fragment, and induction of
           apoptotic cell death catalytic inhibition of protein synthesis in the cytosol.

        -  Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR)
           rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with
           reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis.

        -  Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting
           its CR endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4
           2.5%), and HUS (grade 3-4 6.3%), both reversible.

        -  Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for HCL
           which can consistently eradicate minimal residual disease (MRD), and this is associated
           with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has
           accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the
           treatment of adult patients with HCL.

        -  Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to
           the bacterial-based toxin, and/or had collections of HCL cells not completely eradicated
           by Moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-CD20
           monoclonal antibody (Mab) rituximab or Ruxience to Moxetumomab pasudotox-tdfk.

      Objective:

      -To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab/Ruxience
      used at the planned dose level, in patients with HCL and HCLv.

      Eligibility:

        -  HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1
           month response, at least 1 other therapy.

        -  Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) symptomatic
           splenomegaly, or enlarging HCL mass > 2cm in short axis

        -  Serum creatinine < 1.5 mg/dL, or creatinine clearance greater than or equal to 60 mL/min
           by Cockcroft-Gault equation, where creatinine clearance = (140-age)(kg weight)/(72 x
           Creatinine).

        -  No uncontrolled infection or cardiopulmonary dysfunction

      Design:

        -  Phase I trial, two arm, non-randomized, dose escalation

        -  Administration:

             -  Patients 1-13: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30
                min, Rituximab 375 mg/m^2 iv, 50-400 mg/hr.

             -  Patients 14-26: Moxetumomab pasudotox-tdfk 40 mcg/kg intravenous (iv) over 30 min,
                Ruxience 375 mg/m2 iv, 50-400 mg/hr

             -  Rituximab or Ruxience day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk
                days 1, 3, and 5.

             -  Patients will receive up 4 cycles past documentation of CR without MRD, maximum 8.

             -  To prevent renal toxicity and hypovolemia, patients will be encouraged to drink
                water gradually, approximately 0.5-1 cup/hour or 6L/day, not going >3 hours without
                drinking from days 1 to 8 and to keep a hydration diary to record daily fluid
                consumption.

             -  To prevent rituximab/Ruxience toxicity, patients will receive prophylactic
                dexamethasone orally 0.5- 2 hours before the 1st dose of rituximab, and before
                subsequent doses until rituximab/Ruxience infusion reactions are not seen. Patients
                will also receive diphenhydramine, famotidine, and acetaminophen.

             -  Dexamethasone 4 mg orally (maximum 2 doses/day) will be given as needed to treat
                nausea or fever associated with Moxetumomab pasudotox-tdfk, which might prevent
                adequate water intake

        -  Statistical design:

             -  Up to 26 patients are intended to be treated in the trial. While a total of 26
                evaluable patients will be enrolled, the accrual ceiling will be set at 30 to
                include screen failures and inevaluable patients.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: safety and toxicity
time frame: 4 weeks
description: Determine recommended safe dose of moxetumomab pasudotox-tdfk and rituximab/Ruxience.
measure: Response rates
time frame: 1, 2 and 3.5 years after EOT, then every 2 years
description: Percentage of patients whose cancer shrinks or disappears after treatment
measure: MRD-free rates
time frame: 1, 2 and 3.5 years after EOT, then every 2 years
description: Percentage of patients without minimal residual disease
measure: Response duration
time frame: 1, 2 and 3.5 years after EOT, then every 2 years
description: Time of initial response until documented tumor progression
arm group label: 1 - Dose Escalation
arm group type: Experimental
description: Moxetumomab Pasudotox-tdfk + Rituximab
arm group label: 2- Dose Expansion
arm group type: Experimental
description: Moxetumomab Pasudotox-tdfk + Ruxience
intervention type: Drug
intervention name: Moxetumomab Pasudotox-tdfk
description: Moxetumomab pasudotox-tdfk is administered at 30-40 ug/Kg iv over 30 min given on days 1, 3, 5 of each cycle.
arm group label: 1 - Dose Escalation
arm group label: 2- Dose Expansion
intervention type: Biological
intervention name: Rituximab
description: Rituximab will be administered at 375mg/m^2 iv, 50-400 mg/hr. On cycle 1, Rituximab is given on day -2, on subsequent cycles, Rituximab is given on day 1.
arm group label: 1 - Dose Escalation
intervention type: Biological
intervention name: Ruxience
description: Ruxience will be administered at 375mg/m^2 iv, 50-400 mg/hr. On cycle 1, Ruxience is given on day -2, on subsequent cycles, Ruxience is given on day 1 (Delta)
arm group label: 2- Dose Expansion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Robert J Kreitman, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-C-0042.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Hairy Cell
mesh term: Rituximab
mesh term: Immunotoxin HA22
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data available during the study and indefinitely.
ipd access criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.