<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/NCT02228512</url>
  </required_header>
  <id_info>
    <org_study_id>140176</org_study_id>
    <secondary_id>14-C-0176</secondary_id>
    <nct_id>NCT02228512</nct_id>
  </id_info>
  <brief_title>Study of Pomalidomide Combined With Modified DA-EPOCH and Rituximab in KSHV-Associated Lymphomas</brief_title>
  <official_title>Phase I/II Study of Pomalidomide Combined With Modified DA-EPOCH and Rituximab in KSHV-Associated Lymphomas (Primary Effusion Lymphoma and Large Cell Lymphoma Arising in KSHV-Associated Multicentric Castleman Disease)</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>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - The chemotherapy combination DA-EPOCH-RP includes the drugs etoposide (E), prednisone (P),&#xD;
      vincristine (O), cyclophosphamide (C), doxorubicin (H), rituximab (R), and pomalidomide (P).&#xD;
      Researchers want to see if including pomalidomide will help people with two rare lymphomas.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To study the safety and efficacy of the chemotherapy drugs DA-EPOCH-RP.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Adults at least 18 years old. They must have primary effusion lymphoma or large cell&#xD;
      lymphoma arising from Kaposi sarcoma Herpesvirus-associated multicentric Castleman disease.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be with screened with blood tests, scans, spinal tap, and bone marrow&#xD;
           sample. They may have skin or lymph node samples taken and fluid removed from around&#xD;
           some organs.&#xD;
&#xD;
        -  Participants will have breathing and eye tests. A camera may take pictures inside their&#xD;
           body.&#xD;
&#xD;
        -  Participants will take pomalidomide alone by mouth for up to 21 days. Then they will get&#xD;
           rituximab by intravenous (IV) catheter, which is a small tube that goes into a vein..&#xD;
&#xD;
        -  Participants will have an IV inserted in an arm or chest vein to get the IV chemotherapy&#xD;
           drugs, at the same time the will take pomalidomide by mouth for 5 days.&#xD;
&#xD;
        -  They will get DA-EPOCH-RP in 21-day cycles. Most people will have 6 cycles.&#xD;
&#xD;
        -  They will get 4 study drugs by IV for 5 days and 2 others by mouth for 5 days.&#xD;
&#xD;
        -  They will get daily filgrastim injections in the skin until white blood counts are&#xD;
           acceptable&#xD;
&#xD;
        -  For 2 days of some cycles, methotrexate will be injected into the spinal fluid.&#xD;
&#xD;
        -  After completing EPOCH-RP, some participants who have Kaposi sarcoma will be prescribed&#xD;
           pomalidomide for 3-weeks, followed by a one week break, for up to 12 months.&#xD;
&#xD;
        -  Participants will repeat the blood tests often. They will also have repeated medical&#xD;
           history, physical exam, urine and stool tests, and pictures of any rashes associated&#xD;
           with these lymphomas.&#xD;
&#xD;
        -  Participants will have several follow-up visits over 4 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Kaposi sarcoma herpesvirus (KSHV)-associated primary effusion lymphoma (PEL) and large&#xD;
           cell lymphoma arising from KSHV-MCD are aggressive B cell neoplasms with&#xD;
           clinicopathologic and molecular profiles distinct from other AIDS-related lymphomas.&#xD;
&#xD;
        -  There are no prospective studies on these rare lymphomas. Clinical experience is&#xD;
           limited; however, reported prognosis is poor, with median survival estimated at less&#xD;
           than 6 months using conventional CHOP-like chemotherapy.&#xD;
&#xD;
        -  Novel treatment is urgently needed for KSHV-associated lymphomas, and the therapeutic&#xD;
           approach must take into account concurrent KSHV-associated malignancies which are&#xD;
           commonly seen in this patient population&#xD;
&#xD;
        -  Pomalidomide, an immune-modulatory derivative (IMiD) of thalidomide has in vitro&#xD;
&#xD;
      direct antitumor effect in KSHV-lymphomas as well as immune modulatory and antiangiogenic&#xD;
      effects that may be beneficial in treating both KSHV-NHL and in many patients, concurrent KS.&#xD;
&#xD;
        -  Rituximab, an anti-CD20 monoclonal antibody, has recently been shown to be an active&#xD;
           agent in the management of KSHV-MCD. Although PEL is a CD20-negative tumor, advances in&#xD;
           the understanding the biology of KSHV-infection of B-cells, the pathobiology of IL-6&#xD;
           syndromes in KSHV-MCD and KSHV-NHL, and clinical experience using rituximab in the&#xD;
           treatment of KSHV-MCD support use of rituximab in the treatment of KSHV-NHL, especially&#xD;
           in patients with concurrent KSHV-MCD.&#xD;
&#xD;
        -  Modified dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and&#xD;
           doxorubicin (DA)-EPOCH is an anthracycline-based regimen that allows for personalization&#xD;
           of dose-intensity showing that inclusion of etoposide and infusional administration&#xD;
           decreases tumor cell resistance.&#xD;
&#xD;
        -  The use of DA-EPOCH in combination with rituximab for the treatment of HIVassociated&#xD;
           diffuse large B-cell lymphoma or Burkitt lymphoma has been shown to be safe and&#xD;
           effective.&#xD;
&#xD;
        -  Given the central role of controlling HIV viremia with combination antiretroviral&#xD;
           therapy (cART) in the management of KSHV-associated malignancies, as well as the likely&#xD;
           contribution of uncontrolled HIV viremia to PEL pathogenesis, cART will be employed as&#xD;
           an important part of the treatment regimen.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Phase I:&#xD;
&#xD;
      -Determine the maximum tolerated dose and/or recommended phase II dose of pomalidomide in&#xD;
      combination with DA-EPOCH-R.&#xD;
&#xD;
      Phase II&#xD;
&#xD;
      -Evaluate overall survival in treatment-naive patients with primary effusion lymphoma treated&#xD;
      with pomalidomide in combination with, DA-EPOCH and rituximab (DAEPOCH- RP).&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      -Adult patients greater than or equal to 18 years with pathology confirmed primary effusion&#xD;
      lymphoma,&#xD;
&#xD;
      including extracavitary variant OR large cell lymphoma arising in the setting of&#xD;
      KSHVassociated MCD.&#xD;
&#xD;
        -  Lymphoma that is measurable or assessable&#xD;
&#xD;
        -  Previously treated patients will be allowed if they have not been treated with modified&#xD;
           DA-EPOCH or pomalidomide for KSHV-associated lymphoma&#xD;
&#xD;
        -  Any HIV status&#xD;
&#xD;
        -  Hematologic and biochemical parameters within pre-specified limits at baseline&#xD;
&#xD;
        -  Willing to use effective birth control, as defined in the full protocol&#xD;
&#xD;
        -  Neither pregnant nor breast feeding&#xD;
&#xD;
        -  Excluded if other serious co-morbid condition that would prohibit administration of&#xD;
           planned chemotherapeutic intervention is present&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This is a phase I/ II study of pomalidomide in combination with modified DA-EPOCH-R in&#xD;
           patients with PEL and diffuse large cell lymphoma arising in the setting of KSHVMCD.&#xD;
&#xD;
        -  Phase I of the study will evaluate escalating doses of pomalidomide (3 mg, 4 mg, and 5&#xD;
           mg) in combination with modified DA-EPOCH-R to determine safe and tolerable phase II&#xD;
           pomalidomide dose for combination.&#xD;
&#xD;
        -  Treatment in both Phase I and Phase II will have three parts. Patients will receive up&#xD;
           to 21 days of pomalidomide monotherapy (part A), followed by 6 cycles of pomalidomide in&#xD;
           combination with modified DA-EPOCH-R (part B), and then an optional up to 12 months of&#xD;
           pomalidomide (part C) for patients with concurrent KS, symptomatic KSHVMCD, or KSHV&#xD;
           inflammatory cytokine syndrome (KICS).&#xD;
&#xD;
        -  Patients with HIV will generally be prescribed cART.&#xD;
&#xD;
        -  In phase I, with 3 dose levels, 9-18 patients will be accrued (3-6 patients per level).&#xD;
&#xD;
        -  In the phase II portion of the study, 15 evaluable patients will be enrolled over 48-60&#xD;
           months and 12 months follow-up after the last patient has enrolled, a 1-tailed 0.10&#xD;
           alpha level test would have 80% power to determine if OS curve would demonstrate a&#xD;
           1-year OS consistent with 45% or better and ruling out 20% or worse.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <start_date>August 15, 2014</start_date>
  <completion_date type="Actual">May 5, 2015</completion_date>
  <primary_completion_date type="Actual">May 5, 2015</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>(Phase I) To determine the maximum tolerated dose and/or recommended phase II dose of pomalidomide in combination with DA-EPOCH-R.</measure>
    <time_frame>one-year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>(Phase II) Evaluate overall survival in treatment naive patients with primary effusion lymphoma treated with pomalidomide in combination with modified DA-EPOCH-RP</measure>
    <time_frame>one-year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate response rates and progression free survival</measure>
    <time_frame>one-year</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Large Cell Lymphoma Arising in KSHV-associated Multicentric Castleman Disease</condition>
  <condition>Primary Effusion Lymphoma</condition>
  <arm_group>
    <arm_group_label>1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Treatment naive PEL (main cohort)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Treatment na(SqrRoot) ve large cell lymphoma arising in KSHV-MCD</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Previously treated KSHV-NHL</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pomalidomide</intervention_name>
    <description>Part A: 5 mg po daily for 21 days (full course) Part A: 5 mg po daily for 4 days (short course) Part B: 5 mg po daily for 5 days (Phase I/II dose) Part C: Phase I/II dose) po daily Day 1-21 of 28 day cycle for up to 12 cycles.</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Part A: 375 mg/m2 day 22 (full course) Part A: 375 mg/m2 day 5 (short course) Part A: 375 mg/m2 day 1 (omit pomalidomode) Part B: 375 mg/m2 day 1</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Part B: 60 mg/m2/day po x 5 days (day 1-5</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etoposide</intervention_name>
    <description>Part B: 50 mg/m2/day CIVI over 24 hrs x 4 days</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin</intervention_name>
    <description>Part B: 10 mg/m2/day CIVI over 24 hrs x 4 days</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vincristine</intervention_name>
    <description>Part B: 0.4 mg/m2/day CIVI over 24 hrs x 4 days</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Part B: 750 mg/m2 Day 5</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        2.1.1.1 KSHV-associated non-Hodgkin lymphoma, with pathology reviewed and confirmed at the&#xD;
        NIH. May include WHO recognized tumors&#xD;
&#xD;
        :&#xD;
&#xD;
        2.1.1.1.1 Primary effusion lymphoma (PEL), including extracavitary variant&#xD;
&#xD;
        2.1.1.1.2 Large cell lymphoma arising in the setting of KSHV-associated MCD.&#xD;
&#xD;
        2.1.1.2 Measurable or assessable lymphoma&#xD;
&#xD;
        2.1.1.3 Any HIV status&#xD;
&#xD;
        2.1.1.4 Age 18 years or greater. Because no dosing or adverse event data are currently&#xD;
        available on the use of pomalidomide in combination with EPOCH-R in patients &lt;18 years of&#xD;
        age, children are excluded from this study, but may be eligible for future pediatric&#xD;
        trials.&#xD;
&#xD;
        2.1.1.5 ECOG performance status 0-4.&#xD;
&#xD;
        2.1.1.6 Females of childbearing potential (FCBP) must have a negative serum or urine&#xD;
        pregnancy test with a sensitivity of at least 25 mIU/mL within 14 days prior to and again&#xD;
        within 24 hours before starting pomalidomide and must either commit to continued abstinence&#xD;
        from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly&#xD;
        effective method and one additional effective method AT THE SAME TIME, at least 28 days&#xD;
        before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing.&#xD;
        Men must agree to use a latex condom during sexual contact with a FCBP even if they have&#xD;
        had a vasectomy. All subjects must be counseled at a minimum of every 28 days about&#xD;
        pregnancy precautions and risks of fetal exposure. Risks of Fetal Exposure, Pregnancy&#xD;
        Testing Guidelines and Acceptable Birth Control&#xD;
&#xD;
        2.1.1.7 All study participants must agree to be registered into the mandatory POMALYST REMS&#xD;
        program, and be willing and able to comply with the requirements of the POMALYST REMS&#xD;
        program.&#xD;
&#xD;
        2.1.1.8 Able to take aspirin 81mg orally daily or if intolerant of aspirin, able to take a&#xD;
        substitute thromboprophylaxis such as low molecular weight heparin.&#xD;
&#xD;
        2.1.1.9 Ability of subject to understand and the willingness to sign a written informed&#xD;
        consent document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
        2.1.2.1 Use of other systemic anticancer treatments or agents within the past 2 weeks (4&#xD;
        weeks if the therapy was a monoclonal antibody)&#xD;
&#xD;
        2.1.2.2 Prior dose-adjusted EPOCH or pomalidomide for treatment of KSHV-associated lymphoma&#xD;
&#xD;
        2.1.2.3 Parenchymal brain involvement with lymphoma&#xD;
&#xD;
        2.1.2.4 History of malignant tumors other than KS or KSHV-associated MCD, unless: In&#xD;
        complete remission for greater than or equal to 1 year from the time response was first&#xD;
        documented or&#xD;
&#xD;
          -  Completely resected basal cell carcinoma or&#xD;
&#xD;
          -  In situ squamous cell carcinoma of the cervix or anus&#xD;
&#xD;
        2.1.2.5 Inadequate renal function, defined as calculated or estimated creatinine clearance&#xD;
        &lt; 60 mL/min unless lymphoma related&#xD;
&#xD;
        2.1.2.6 Inadequate hepatic function:&#xD;
&#xD;
        --2.1.2.6.1 Bilirubin (total) &gt; 1.5 times the upper limit of normal; AST and/or ALT &gt; 3&#xD;
        times the upper limit of normal; EXCEPTIONS:&#xD;
&#xD;
          -  Total bilirubin greater than or equal to 5 mg/dL in patients with Gilbert's syndrome&#xD;
             as defined by &gt;80% unconjugated&#xD;
&#xD;
          -  Total bilirubin greater than or equal to 7.5 with direct fraction &gt; 0.7 if patient is&#xD;
             receiving a protease inhibitor at the time of initial evaluation&#xD;
&#xD;
          -  Hepatic dysfunction attributed to lymphoma&#xD;
&#xD;
        2.1.2.7 ANC &lt;1000/mm3 and platelets &lt; 75,000/mm3 unless lymphoma, KSHV-MCD, or KICS-&#xD;
        related.&#xD;
&#xD;
        2.1.2.8 CTCAEv4.0 Grade 3-4 neuropathy&#xD;
&#xD;
        2.1.2.9 Ejection fraction less than 40% by echocardiography&#xD;
&#xD;
        2.1.2.10 Known drug-related, inherited, or acquired procoagulant disorder including&#xD;
        prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein&#xD;
        S deficiency and antiphospholipid syndrome but not including heterozygosity for the Factor&#xD;
        V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria&#xD;
        for the antiphospholipid syndrome.&#xD;
&#xD;
        2.1.2.11 History of hypersensitivity reactions attributed to thalidomide, lenalidomide, or&#xD;
        pomalidomide, including prior development of erythema nodosum if characterized by a&#xD;
        desquamating rash while taking thalidomide, lenalidomide, or pomalidomide.&#xD;
&#xD;
        2.1.2.12 Breast feeding (if lactating, must agree not to breast feed while taking&#xD;
        pomalidomide). Because there is an unknown but potential risk for adverse events in nursing&#xD;
        infants secondary to treatment of the mother with Pomalidomide, breastfeeding should be&#xD;
        discontinued if the mother is treated with Pomalidomide.&#xD;
&#xD;
        2.1.2.13 Uncontrolled severe intercurrent illness including, but not limited to: bacterial,&#xD;
        fungal, or life-threatening viral infection; symptomatic congestive heart failure; unstable&#xD;
        angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would&#xD;
        limit compliance with study requirements.&#xD;
&#xD;
        2.1.2.14 Any condition, including laboratory abnormalities, which in the opinion of the&#xD;
        Principal Investigator or Lead Associate Investigator, would prohibit administration of&#xD;
        planned chemotherapeutic intervention, places the subject at unacceptable risk if they were&#xD;
        to participate in the study or confounds the ability to interpret data from the study&#xD;
&#xD;
        2.1.2.15 Pregnant women are excluded from this study because pomalidomide is a Category X&#xD;
        agent with the potential for teratogenic or abortifacient effects. These potential risks&#xD;
        may also apply to other agents used in this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas S Uldrick, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <reference>
    <citation>Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, Weiss RA, Isaacson PG, Boshoff C. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000 Feb 15;95(4):1406-12.</citation>
    <PMID>10666218</PMID>
  </reference>
  <reference>
    <citation>Nador RG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Sald J, Knowles DM. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood. 1996 Jul 15;88(2):645-56.</citation>
    <PMID>8695812</PMID>
  </reference>
  <reference>
    <citation>Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995 May 4;332(18):1186-91. doi: 10.1056/NEJM199505043321802.</citation>
    <PMID>7700311</PMID>
  </reference>
  <verification_date>May 5, 2015</verification_date>
  <study_first_submitted>August 27, 2014</study_first_submitted>
  <study_first_submitted_qc>August 27, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2014</study_first_posted>
  <last_update_submitted>August 29, 2018</last_update_submitted>
  <last_update_submitted_qc>August 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HHV8</keyword>
  <keyword>PEL</keyword>
  <keyword>Immune Modulation</keyword>
  <keyword>CC-4047</keyword>
  <keyword>IMiD</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Primary Effusion</mesh_term>
    <mesh_term>Castleman Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Etoposide</mesh_term>
    <mesh_term>Vincristine</mesh_term>
    <mesh_term>Pomalidomide</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/NCT02228512
org study id: 140176
secondary id: 14-C-0176
nct id: NCT02228512
lead sponsor: 
Background:

      - The chemotherapy combination DA-EPOCH-RP includes the drugs etoposide (E), prednisone (P),
      vincristine (O), cyclophosphamide (C), doxorubicin (H), rituximab (R), and pomalidomide (P).
      Researchers want to see if including pomalidomide will help people with two rare lymphomas.

      Objectives:

      - To study the safety and efficacy of the chemotherapy drugs DA-EPOCH-RP.

      Eligibility:

      - Adults at least 18 years old. They must have primary effusion lymphoma or large cell
      lymphoma arising from Kaposi sarcoma Herpesvirus-associated multicentric Castleman disease.

      Design:

        -  Participants will be with screened with blood tests, scans, spinal tap, and bone marrow
           sample. They may have skin or lymph node samples taken and fluid removed from around
           some organs.

        -  Participants will have breathing and eye tests. A camera may take pictures inside their
           body.

        -  Participants will take pomalidomide alone by mouth for up to 21 days. Then they will get
           rituximab by intravenous (IV) catheter, which is a small tube that goes into a vein..

        -  Participants will have an IV inserted in an arm or chest vein to get the IV chemotherapy
           drugs, at the same time the will take pomalidomide by mouth for 5 days.

        -  They will get DA-EPOCH-RP in 21-day cycles. Most people will have 6 cycles.

        -  They will get 4 study drugs by IV for 5 days and 2 others by mouth for 5 days.

        -  They will get daily filgrastim injections in the skin until white blood counts are
           acceptable

        -  For 2 days of some cycles, methotrexate will be injected into the spinal fluid.

        -  After completing EPOCH-RP, some participants who have Kaposi sarcoma will be prescribed
           pomalidomide for 3-weeks, followed by a one week break, for up to 12 months.

        -  Participants will repeat the blood tests often. They will also have repeated medical
           history, physical exam, urine and stool tests, and pictures of any rashes associated
           with these lymphomas.

        -  Participants will have several follow-up visits over 4 years.
Background:

        -  Kaposi sarcoma herpesvirus (KSHV)-associated primary effusion lymphoma (PEL) and large
           cell lymphoma arising from KSHV-MCD are aggressive B cell neoplasms with
           clinicopathologic and molecular profiles distinct from other AIDS-related lymphomas.

        -  There are no prospective studies on these rare lymphomas. Clinical experience is
           limited; however, reported prognosis is poor, with median survival estimated at less
           than 6 months using conventional CHOP-like chemotherapy.

        -  Novel treatment is urgently needed for KSHV-associated lymphomas, and the therapeutic
           approach must take into account concurrent KSHV-associated malignancies which are
           commonly seen in this patient population

        -  Pomalidomide, an immune-modulatory derivative (IMiD) of thalidomide has in vitro

      direct antitumor effect in KSHV-lymphomas as well as immune modulatory and antiangiogenic
      effects that may be beneficial in treating both KSHV-NHL and in many patients, concurrent KS.

        -  Rituximab, an anti-CD20 monoclonal antibody, has recently been shown to be an active
           agent in the management of KSHV-MCD. Although PEL is a CD20-negative tumor, advances in
           the understanding the biology of KSHV-infection of B-cells, the pathobiology of IL-6
           syndromes in KSHV-MCD and KSHV-NHL, and clinical experience using rituximab in the
           treatment of KSHV-MCD support use of rituximab in the treatment of KSHV-NHL, especially
           in patients with concurrent KSHV-MCD.

        -  Modified dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and
           doxorubicin (DA)-EPOCH is an anthracycline-based regimen that allows for personalization
           of dose-intensity showing that inclusion of etoposide and infusional administration
           decreases tumor cell resistance.

        -  The use of DA-EPOCH in combination with rituximab for the treatment of HIVassociated
           diffuse large B-cell lymphoma or Burkitt lymphoma has been shown to be safe and
           effective.

        -  Given the central role of controlling HIV viremia with combination antiretroviral
           therapy (cART) in the management of KSHV-associated malignancies, as well as the likely
           contribution of uncontrolled HIV viremia to PEL pathogenesis, cART will be employed as
           an important part of the treatment regimen.

      Objectives:

      Phase I:

      -Determine the maximum tolerated dose and/or recommended phase II dose of pomalidomide in
      combination with DA-EPOCH-R.

      Phase II

      -Evaluate overall survival in treatment-naive patients with primary effusion lymphoma treated
      with pomalidomide in combination with, DA-EPOCH and rituximab (DAEPOCH- RP).

      Eligibility:

      -Adult patients greater than or equal to 18 years with pathology confirmed primary effusion
      lymphoma,

      including extracavitary variant OR large cell lymphoma arising in the setting of
      KSHVassociated MCD.

        -  Lymphoma that is measurable or assessable

        -  Previously treated patients will be allowed if they have not been treated with modified
           DA-EPOCH or pomalidomide for KSHV-associated lymphoma

        -  Any HIV status

        -  Hematologic and biochemical parameters within pre-specified limits at baseline

        -  Willing to use effective birth control, as defined in the full protocol

        -  Neither pregnant nor breast feeding

        -  Excluded if other serious co-morbid condition that would prohibit administration of
           planned chemotherapeutic intervention is present

      Design:

        -  This is a phase I/ II study of pomalidomide in combination with modified DA-EPOCH-R in
           patients with PEL and diffuse large cell lymphoma arising in the setting of KSHVMCD.

        -  Phase I of the study will evaluate escalating doses of pomalidomide (3 mg, 4 mg, and 5
           mg) in combination with modified DA-EPOCH-R to determine safe and tolerable phase II
           pomalidomide dose for combination.

        -  Treatment in both Phase I and Phase II will have three parts. Patients will receive up
           to 21 days of pomalidomide monotherapy (part A), followed by 6 cycles of pomalidomide in
           combination with modified DA-EPOCH-R (part B), and then an optional up to 12 months of
           pomalidomide (part C) for patients with concurrent KS, symptomatic KSHVMCD, or KSHV
           inflammatory cytokine syndrome (KICS).

        -  Patients with HIV will generally be prescribed cART.

        -  In phase I, with 3 dose levels, 9-18 patients will be accrued (3-6 patients per level).

        -  In the phase II portion of the study, 15 evaluable patients will be enrolled over 48-60
           months and 12 months follow-up after the last patient has enrolled, a 1-tailed 0.10
           alpha level test would have 80% power to determine if OS curve would demonstrate a
           1-year OS consistent with 45% or better and ruling out 20% or worse.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: (Phase I) To determine the maximum tolerated dose and/or recommended phase II dose of pomalidomide in combination with DA-EPOCH-R.
time frame: one-year
measure: (Phase II) Evaluate overall survival in treatment naive patients with primary effusion lymphoma treated with pomalidomide in combination with modified DA-EPOCH-RP
time frame: one-year
measure: Evaluate response rates and progression free survival
time frame: one-year
arm group label: 1
arm group type: Active Comparator
description: Treatment naive PEL (main cohort)
arm group label: 2
arm group type: Active Comparator
description: Treatment na(SqrRoot) ve large cell lymphoma arising in KSHV-MCD
arm group label: 3
arm group type: Active Comparator
description: Previously treated KSHV-NHL
intervention type: Drug
intervention name: Pomalidomide
description: Part A: 5 mg po daily for 21 days (full course) Part A: 5 mg po daily for 4 days (short course) Part B: 5 mg po daily for 5 days (Phase I/II dose) Part C: Phase I/II dose) po daily Day 1-21 of 28 day cycle for up to 12 cycles.
arm group label: 1
arm group label: 2
arm group label: 3
intervention type: Drug
intervention name: Rituximab
description: Part A: 375 mg/m2 day 22 (full course) Part A: 375 mg/m2 day 5 (short course) Part A: 375 mg/m2 day 1 (omit pomalidomode) Part B: 375 mg/m2 day 1
arm group label: 1
arm group label: 2
arm group label: 3
intervention type: Drug
intervention name: Prednisone
description: Part B: 60 mg/m2/day po x 5 days (day 1-5
arm group label: 1
arm group label: 2
arm group label: 3
intervention type: Drug
intervention name: Etoposide
description: Part B: 50 mg/m2/day CIVI over 24 hrs x 4 days
arm group label: 1
arm group label: 2
arm group label: 3
intervention type: Drug
intervention name: Doxorubicin
description: Part B: 10 mg/m2/day CIVI over 24 hrs x 4 days
arm group label: 1
arm group label: 2
arm group label: 3
intervention type: Drug
intervention name: Vincristine
description: Part B: 0.4 mg/m2/day CIVI over 24 hrs x 4 days
arm group label: 1
arm group label: 2
arm group label: 3
intervention type: Drug
intervention name: Cyclophosphamide
description: Part B: 750 mg/m2 Day 5
arm group label: 1
arm group label: 2
arm group label: 3
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Thomas S Uldrick, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
country: United States
citation: Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, Weiss RA, Isaacson PG, Boshoff C. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000 Feb 15;95(4):1406-12.
PMID: 10666218
citation: Nador RG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Sald J, Knowles DM. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood. 1996 Jul 15;88(2):645-56.
PMID: 8695812
citation: Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med. 1995 May 4;332(18):1186-91. doi: 10.1056/NEJM199505043321802.
PMID: 7700311
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Primary Effusion
mesh term: Castleman Disease
mesh term: Prednisone
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Doxorubicin
mesh term: Etoposide
mesh term: Vincristine
mesh term: Pomalidomide