<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/NCT04447027</url>
  </required_header>
  <id_info>
    <org_study_id>200127</org_study_id>
    <secondary_id>20-C-0127</secondary_id>
    <nct_id>NCT04447027</nct_id>
  </id_info>
  <brief_title>Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies</brief_title>
  <official_title>A Phase 1 Study of Romidepsin, CC-486 (5-azacitidine), Dexamethasone, and Lenalidomide (RAdR) for Relapsed/Refractory T-cell Malignancies</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;
      Mature T-cell malignancies (TCMs) are a rare group of cancers that usually do not have&#xD;
      effective treatments or cures. Because of this, participants with TCMs often relapse and have&#xD;
      a poor overall prognosis. This trial is testing if combining several drugs against TCMs can&#xD;
      be a more effective.&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
      To test if the combination of romidepsin, CC-486 (5-azacitidine), dexamethasone, and&#xD;
      lenalidomide (RAdR) can be given safely to participants with relapsed or treatment refractory&#xD;
      TCM.&#xD;
&#xD;
      Other (Secondary) Objective:&#xD;
&#xD;
      Measure the activity of this combination treatment.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People age 18 and older who have a failed or relapsed after standard treatments for mature&#xD;
      TCMs.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened for eligibility by performing the following tests or&#xD;
      procedures:&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Medicine review&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Symptom review&#xD;
&#xD;
      Bone marrow examination&#xD;
&#xD;
      Total Body imaging scans or x-rays&#xD;
&#xD;
      Tumor biopsy&#xD;
&#xD;
      Participants will have blood tests during treatment to make sure their blood cell counts are&#xD;
      okay.&#xD;
&#xD;
      Romidepsin is infused through an IV placed in one of the veins usually in the arm.&#xD;
      Lenalidomide, dexamethasone, and CC-486 (5-azacitidine) are pills or capsules taken by mouth.&#xD;
&#xD;
      Participants are asked to keep a diary of when they take their pills to make sure they are&#xD;
      taking these medicines properly.&#xD;
&#xD;
      Participants will have tumor imaging scans after every 2nd cycle (or 6 weeks) to check if the&#xD;
      treatment is working. If the doctors are concerned the cancer has spread to the brain and/or&#xD;
      spine, they will have scans of the area(s) and a sampling of the fluid around the brain/spine&#xD;
      which is obtained through a small needle inserted into the lower part of the back for a short&#xD;
      time to collect the fluid. This procedure is called a spinal tap or lumbar puncture.&#xD;
&#xD;
      Participants who have tumor in their skin will have repeat exams of their skin and sometimes&#xD;
      photographs taken of these areas to see if the treatment is working.&#xD;
&#xD;
      Participants will also be asked to give blood, saliva, and sometimes have optional biopsies&#xD;
      of their tumor where these tests are done for research purposes.&#xD;
&#xD;
      After they have completed the protocol treatment (6 cycles), they will be asked to return to&#xD;
      clinic 30 days after treatment has ended, then every other month (or 60 days) for the first 6&#xD;
      months, then every 3 months (90 days) for 2 years, and then every 6 months for years 2 to 4&#xD;
      after completing treatment. After 4.5 years, they will be seen once a year.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Mature T-cell malignancies (TCM) are rare and heterogeneous group of leukemias and&#xD;
           lymphomas accounting for 5 to 10% of all lymphomas in the US&#xD;
&#xD;
        -  Patients with systemic TCM are most commonly treated with a CHOP (cyclophosphamide,&#xD;
           doxorubicin, vincristine and prednisone)-like regimens, that produce long-term&#xD;
           progression-free survival in about 30% of these cases&#xD;
&#xD;
        -  Patients with relapsed/refractory (R/R) TCM have very poor prognosis with median overall&#xD;
           survival of less than 1 year. Treatment options for R/R TCM are very few and of limited&#xD;
           efficacy, thus novel treatment strategies are urgently needed.&#xD;
&#xD;
        -  Mutations in epigenetic regulators are common in aggressive TCMs and standard treatment&#xD;
           with histone deacetylase inhibitors (HDACi) such as romidepsin show modest clinical&#xD;
           activity with single agent the overall response (ORR) around 25%&#xD;
&#xD;
        -  Combination of romidepsin and 5-azacitidine (hypomethylating agents) was synergistic in&#xD;
           preclinical models, and has demonstrated high clinical activity with an ORR of 79%&#xD;
&#xD;
        -  Many TCMs rely on The Ikaros-dependent NF-kB/IRF4 signaling pathway to maintain&#xD;
           proliferation, which is why lenalidomide, which induces degradation of Ikaros and&#xD;
           downregulates IRF4, has single agent activity in R/R TCM with ORR of 26% to 42%,&#xD;
           depending on the subtype.&#xD;
&#xD;
        -  Lenalidomide synergizes with romidepsin and enhances tumor cell death in TCM cell lines,&#xD;
           predicting that the addition of lenalidomide to the established romidepsin/ CC-486&#xD;
           (5-azacitidine) combination will further improve efficacy.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      -To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of the&#xD;
      four drug combination of CC-486 (5-azacitidine), romidepsin, lenalidomide and dexamethasone&#xD;
      in patients with TCM&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Refractory/relapsed TCM (excluding in Cutaneous T-Cell Lymphoma) defined as follows:&#xD;
&#xD;
             -  Patients with systemic disease&#xD;
&#xD;
             -  Have received at least one line of prior therapy&#xD;
&#xD;
             -  Must have received brentuximab vedotin if the disease is anaplastic large cell&#xD;
                lymphoma or CD30-positive cutaneous T-cell lymphoma&#xD;
&#xD;
        -  Age &gt;= 18 years of age&#xD;
&#xD;
        -  ECOG performance status of &lt;= 2 (or &lt;= 3 if decrease is due to the disease)&#xD;
&#xD;
        -  Histologically or cytologically confirmed relapsed and/or refractory mature TCM&#xD;
&#xD;
        -  Adequate organ and marrow function&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Open-label, single-center, uncontrolled Phase 1 study&#xD;
&#xD;
        -  3 + 3 design will be used to determine the MTD of dose-escalated lenalidomide with fixed&#xD;
           dose of romidepsin and CC-486 (5-azacitidine)&#xD;
&#xD;
        -  An expansion cohort of 9 patients will be evaluated at the MTD&#xD;
&#xD;
        -  Maximum 6 cycles (28-day cycle) of combination therapy&#xD;
&#xD;
        -  To explore all dose levels, including further evaluation in a dose expansion cohort, the&#xD;
           accrual ceiling will be set at 30 patients&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 17, 2020</start_date>
  <completion_date type="Anticipated">May 15, 2025</completion_date>
  <primary_completion_date type="Anticipated">November 15, 2024</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>Maximum tolerated dose (MTD)</measure>
    <time_frame>21 days</time_frame>
    <description>Frequency (number and percentage) of treatment emergent adverse events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>safety and tolerability</measure>
    <time_frame>6 cycles</time_frame>
    <description>rate and severity of AEs will be summarized by grade and type of toxicity</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Repsonse Rate</measure>
    <time_frame>6 cycles</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response Rate</measure>
    <time_frame>6 cycles</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually</time_frame>
    <description>The response rate will be determined and reported along with a 95% confidence interval</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Cutaneous T-Cell Lymphoma</condition>
  <condition>Mature T-cell Malignancies</condition>
  <condition>Peripheral T-Cell Lymphoma</condition>
  <condition>Relapsed/ Refractory T-cell Malignancies</condition>
  <arm_group>
    <arm_group_label>1- Experimental Treatment: Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2 - Experimental Treatment: Dose Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Romidepsin</intervention_name>
    <description>Romidepsin (12mg/ m2 ) will be administered on days 1 and 10 of each cycle through a peripheral or central intravenous catheter for 6 cycles.</description>
    <arm_group_label>1- Experimental Treatment: Dose Escalation</arm_group_label>
    <arm_group_label>2 - Experimental Treatment: Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>Lenalidomide will be administered by oral intake in a dose-escalation with a starting dose of 5mg daily, a second dose level of 10mg daily, a third dose level at 15mg daily, and a fourth dose level at 20mg daily on days -7 to day 10 of first cycle. After the second cycle, lenalidomide will be given from day 1 to day 10 in each cycle for up to 6 cycles.</description>
    <arm_group_label>1- Experimental Treatment: Dose Escalation</arm_group_label>
    <arm_group_label>2 - Experimental Treatment: Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CC-486 (5-azacitidine)</intervention_name>
    <description>CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 6 cycles.</description>
    <arm_group_label>1- Experimental Treatment: Dose Escalation</arm_group_label>
    <arm_group_label>2 - Experimental Treatment: Dose Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Dexamethasone, 40mg, PO, will be given on days 1 and 10 of each cycle.</description>
    <arm_group_label>1- Experimental Treatment: Dose Escalation</arm_group_label>
    <arm_group_label>2 - Experimental Treatment: Dose Expansion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients must have relapsed after or progressed during at least one line of prior&#xD;
             systemic therapy (which may include allogeneic stem cell transplantation) for mature T&#xD;
             or NK/T neoplasm, i.e. have relapsed and/or refractory mature T and NK neoplasm per&#xD;
             2016 WHO classification excluding chronic lymphoproliferative disorder of NK cells,&#xD;
             aggressive NK-cell leukemia, and Cutaneous T-Cell Lymphoma.&#xD;
&#xD;
          -  T or NK/T neoplasm from initial diagnosis or recurrence must be histologically or&#xD;
             cytologically proven and diagnosis be confirmed by the Laboratory of Pathology, NCI,&#xD;
&#xD;
          -  Patients with ALCL or CD30 positive MF/SS must have relapsed after or become&#xD;
             intolerant to prior anti-CD30 targeting therapy treatment with brentuximab vedotin&#xD;
&#xD;
          -  For patients without circulating leukemia/lymphoma cells detectable by flow cytometry,&#xD;
             a formalin fixed tissue block or 15 slides of tumor sample (archival or fresh) must be&#xD;
             available at enrollment for performance of correlative studies. NOTE: Patients without&#xD;
             circulating malignant cells must be willing to have a tumor biopsy if prior tissue or&#xD;
             adequate archival tissue is not available (i.e., post-enrollment and prior to&#xD;
             treatment).&#xD;
&#xD;
          -  Disease must be measurable with at least one measurable lesion by RECIL 2017 or mSWAT&#xD;
             criteria, or have an abnormal clonal T-cell population detectable by peripheral blood&#xD;
             flow cytometry&#xD;
&#xD;
          -  Age &gt;18 years&#xD;
&#xD;
          -  ECOG performance status &lt;=2, or &lt;= 3 if the decreased performance status is deemed to&#xD;
             be due to disease and not residual toxicity from prior therapy or other causes.&#xD;
&#xD;
          -  Adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Absolute neutrophil count &gt;= 1,000/mcL&#xD;
&#xD;
               -  Platelets &gt;= 75,000/mcL&#xD;
&#xD;
               -  Total bilirubin &lt;= 1.5 X institutional upper limit of normal (ULN)&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) &lt;= 2.5 X institutional ULN&#xD;
&#xD;
               -  Serum Creatinine &lt;= 1.5 mg/dL OR&#xD;
&#xD;
               -  Creatinine Clearance &gt;= 60 mL/min/1.73 m^2 as calculated by direct measurement of&#xD;
                  24-hour urine for creatinine clearance&#xD;
&#xD;
          -  Negative serum or urine pregnancy test at screening for women of childbearing&#xD;
             potential (WOCBP) NOTE: WOCBP is defined as any female who has experienced menarche&#xD;
             and who has not undergone successful surgical sterilization or who is not&#xD;
             postmenopausal. WOCBP must have a negative pregnancy test (HCG blood or urine) during&#xD;
             screening.&#xD;
&#xD;
          -  All study participants must be registered into the mandatory Revlimid REMS(R) program&#xD;
             and be willing and able to comply with the requirements of the REMS(R) program.&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for&#xD;
             the duration of study participation, and for at least 6 months after completion of&#xD;
             treatment for women, and for at least 3 months after completion of treatment for men.&#xD;
             Females of reproductive potential must adhere to the scheduled pregnancy testing as&#xD;
             required in the Revlimid REMS(R) program.&#xD;
&#xD;
          -  Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents.&#xD;
&#xD;
          -  Anti-cancer treatment within 2 weeks prior to enrollment. (4 weeks for monoclonal&#xD;
             antibodies and 6 weeks for nitrosoureas or mitomycin C).&#xD;
&#xD;
          -  Patients who have received two of the following drugs at any point: lenalidomide,&#xD;
             romidepsin, and 5-azacitidine. Patients who have received only one of the three drugs&#xD;
             remain eligible.&#xD;
&#xD;
          -  Patients with a diagnosis of CTCL are excluded from participation in the expansion&#xD;
             cohort.&#xD;
&#xD;
          -  Other malignancy that requires ongoing systemic hormonal therapy, chemotherapy, or&#xD;
             immunotherapy.&#xD;
&#xD;
          -  History of allergic reactions or known or suspected hypersensitivity attributed to&#xD;
             compounds of similar chemical or biologic composition to lenalidomide, romidepsin and&#xD;
             5-azacitidine&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing&#xD;
             or active infection requiring systemic therapy, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirements.&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral&#xD;
             therapy with undetectable viral load within 6 months are eligible for this trial.&#xD;
&#xD;
          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral&#xD;
             load must be undetectable on suppressive therapy, if indicated.&#xD;
&#xD;
          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated&#xD;
             and cured. For patients with HCV infection who are currently on treatment, they are&#xD;
             eligible if they have an undetectable HCV viral load.&#xD;
&#xD;
          -  History of inflammatory bowel disease (e.g., Crohn s disease, ulcerative colitis),&#xD;
             celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other&#xD;
             gastrointestinal disorder or defect that would interfere with the absorption,&#xD;
             distribution, metabolism or excretion of the study drug and/or predispose the subject&#xD;
             to an increased risk of gastrointestinal toxicity.&#xD;
&#xD;
          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular&#xD;
             accident/stroke (&lt; 6 months prior to enrollment), myocardial infarction (&lt; 6 months&#xD;
             prior to enrollment), unstable angina, congestive heart failure (&gt;= New York Heart&#xD;
             Association Classification Class II), congenital long QT syndrome, or other serious&#xD;
             cardiac arrhythmia including 2nd degree atrio ventricular (AV) block type II, 3rd&#xD;
             degree AV block, or bradycardia (ventricular rate less than 50 beats/min).&#xD;
&#xD;
          -  Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other&#xD;
             causes.&#xD;
&#xD;
          -  Uncontrolled hypertension, i.e., blood pressure (BP) of &gt;=160/95; patients who have a&#xD;
             history of hypertension controlled by medication must be on a stable dose (for at&#xD;
             least one month) and meet all other inclusion criteria.&#xD;
&#xD;
          -  Triplicate average baseline QTcF interval &gt;= 480 ms&#xD;
&#xD;
          -  Patients taking drugs leading to significant QT prolongation Note: A 5 half-life&#xD;
             washout period must have elapsed following the use of these drugs prior to&#xD;
             administration of romidepsin.&#xD;
&#xD;
          -  Concomitant use of rifampin and other strong CYP3A4 inhibitors and inducers within 2&#xD;
             weeks prior to starting protocol therapy.&#xD;
&#xD;
          -  Other severe acute or chronic medical conditions including psychiatric conditions such&#xD;
             as recent (within the past year) or active suicidal ideation or behavior; or&#xD;
             laboratory abnormalities that may increase the risk associated with study&#xD;
             participation or study treatment administration or may interfere with the&#xD;
             interpretation of study results and, in the judgment of the investigator, would make&#xD;
             the patient inappropriate for entry into this study.&#xD;
&#xD;
          -  Pregnant or lactating women. Pregnant women are excluded from this study because&#xD;
             lenalidomide is a Class X agent with the potential for teratogenic or abortifacient&#xD;
             effects. Because there is an unknown but potential risk for adverse events in nursing&#xD;
             infants secondary to treatment of the mother with lenalidomide, breastfeeding should&#xD;
             be discontinued if the mother is treated with lenalidomide. These potential risks may&#xD;
             also apply to other agents used in this study.&#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>Mark J Roschewski, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>NCI Medical Oncology Referral Office</last_name>
    <phone>(240) 760-6050</phone>
    <email>ncimo_referrals@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mark J Roschewski, M.D.</last_name>
    <phone>(240) 760-6183</phone>
    <email>mark.roschewski@nih.gov</email>
  </overall_contact_backup>
  <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>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact National Cancer Institute Referral Office</last_name>
      <phone>888-624-1937</phone>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2020-C-0127.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>August 15, 2023</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>August 16, 2023</last_update_submitted>
  <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Immunomodulatory Drugs (IMiDs)</keyword>
  <keyword>TCM</keyword>
  <keyword>ALCL</keyword>
  <keyword>Histone Deacetylase Inhibitors (HDACi)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Lymphoma, T-Cell</mesh_term>
    <mesh_term>Lymphoma, T-Cell, Peripheral</mesh_term>
    <mesh_term>Lymphoma, T-Cell, Cutaneous</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Lenalidomide</mesh_term>
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Romidepsin</mesh_term>
    <mesh_term>Cc-486</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. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.</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 will be available during the study and indefinitely. @@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.</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/NCT04447027
org study id: 200127
secondary id: 20-C-0127
nct id: NCT04447027
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Mature T-cell malignancies (TCMs) are a rare group of cancers that usually do not have
      effective treatments or cures. Because of this, participants with TCMs often relapse and have
      a poor overall prognosis. This trial is testing if combining several drugs against TCMs can
      be a more effective.

      Primary Objective:

      To test if the combination of romidepsin, CC-486 (5-azacitidine), dexamethasone, and
      lenalidomide (RAdR) can be given safely to participants with relapsed or treatment refractory
      TCM.

      Other (Secondary) Objective:

      Measure the activity of this combination treatment.

      Eligibility:

      People age 18 and older who have a failed or relapsed after standard treatments for mature
      TCMs.

      Design:

      Participants will be screened for eligibility by performing the following tests or
      procedures:

      Physical exam

      Medical history

      Medicine review

      Blood and urine tests

      Symptom review

      Bone marrow examination

      Total Body imaging scans or x-rays

      Tumor biopsy

      Participants will have blood tests during treatment to make sure their blood cell counts are
      okay.

      Romidepsin is infused through an IV placed in one of the veins usually in the arm.
      Lenalidomide, dexamethasone, and CC-486 (5-azacitidine) are pills or capsules taken by mouth.

      Participants are asked to keep a diary of when they take their pills to make sure they are
      taking these medicines properly.

      Participants will have tumor imaging scans after every 2nd cycle (or 6 weeks) to check if the
      treatment is working. If the doctors are concerned the cancer has spread to the brain and/or
      spine, they will have scans of the area(s) and a sampling of the fluid around the brain/spine
      which is obtained through a small needle inserted into the lower part of the back for a short
      time to collect the fluid. This procedure is called a spinal tap or lumbar puncture.

      Participants who have tumor in their skin will have repeat exams of their skin and sometimes
      photographs taken of these areas to see if the treatment is working.

      Participants will also be asked to give blood, saliva, and sometimes have optional biopsies
      of their tumor where these tests are done for research purposes.

      After they have completed the protocol treatment (6 cycles), they will be asked to return to
      clinic 30 days after treatment has ended, then every other month (or 60 days) for the first 6
      months, then every 3 months (90 days) for 2 years, and then every 6 months for years 2 to 4
      after completing treatment. After 4.5 years, they will be seen once a year.
Background:

        -  Mature T-cell malignancies (TCM) are rare and heterogeneous group of leukemias and
           lymphomas accounting for 5 to 10% of all lymphomas in the US

        -  Patients with systemic TCM are most commonly treated with a CHOP (cyclophosphamide,
           doxorubicin, vincristine and prednisone)-like regimens, that produce long-term
           progression-free survival in about 30% of these cases

        -  Patients with relapsed/refractory (R/R) TCM have very poor prognosis with median overall
           survival of less than 1 year. Treatment options for R/R TCM are very few and of limited
           efficacy, thus novel treatment strategies are urgently needed.

        -  Mutations in epigenetic regulators are common in aggressive TCMs and standard treatment
           with histone deacetylase inhibitors (HDACi) such as romidepsin show modest clinical
           activity with single agent the overall response (ORR) around 25%

        -  Combination of romidepsin and 5-azacitidine (hypomethylating agents) was synergistic in
           preclinical models, and has demonstrated high clinical activity with an ORR of 79%

        -  Many TCMs rely on The Ikaros-dependent NF-kB/IRF4 signaling pathway to maintain
           proliferation, which is why lenalidomide, which induces degradation of Ikaros and
           downregulates IRF4, has single agent activity in R/R TCM with ORR of 26% to 42%,
           depending on the subtype.

        -  Lenalidomide synergizes with romidepsin and enhances tumor cell death in TCM cell lines,
           predicting that the addition of lenalidomide to the established romidepsin/ CC-486
           (5-azacitidine) combination will further improve efficacy.

      Objectives:

      -To determine the safety and toxicity profile and the maximum tolerated dose (MTD) of the
      four drug combination of CC-486 (5-azacitidine), romidepsin, lenalidomide and dexamethasone
      in patients with TCM

      Eligibility:

        -  Refractory/relapsed TCM (excluding in Cutaneous T-Cell Lymphoma) defined as follows:

             -  Patients with systemic disease

             -  Have received at least one line of prior therapy

             -  Must have received brentuximab vedotin if the disease is anaplastic large cell
                lymphoma or CD30-positive cutaneous T-cell lymphoma

        -  Age >= 18 years of age

        -  ECOG performance status of <= 2 (or <= 3 if decrease is due to the disease)

        -  Histologically or cytologically confirmed relapsed and/or refractory mature TCM

        -  Adequate organ and marrow function

      Design:

        -  Open-label, single-center, uncontrolled Phase 1 study

        -  3 + 3 design will be used to determine the MTD of dose-escalated lenalidomide with fixed
           dose of romidepsin and CC-486 (5-azacitidine)

        -  An expansion cohort of 9 patients will be evaluated at the MTD

        -  Maximum 6 cycles (28-day cycle) of combination therapy

        -  To explore all dose levels, including further evaluation in a dose expansion cohort, the
           accrual ceiling will be set at 30 patients
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD)
time frame: 21 days
description: Frequency (number and percentage) of treatment emergent adverse events
measure: safety and tolerability
time frame: 6 cycles
description: rate and severity of AEs will be summarized by grade and type of toxicity
measure: Overall Repsonse Rate
time frame: 6 cycles
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Progression-free survival
time frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Complete Response Rate
time frame: 6 cycles
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Duration of response (DOR)
time frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually
description: The response rate will be determined and reported along with a 95% confidence interval
measure: Overall Survival (OS)
time frame: every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually
description: The response rate will be determined and reported along with a 95% confidence interval
arm group label: 1- Experimental Treatment: Dose Escalation
arm group type: Experimental
description: Lenalidomide by oral intake at escalating doses of 5, 10, 15, or 20 mg/day on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle, to determine MTD
arm group label: 2 - Experimental Treatment: Dose Expansion
arm group type: Experimental
description: Lenalidomide by oral intake at MTD on days -7 to 10 of each 21-day cycle (max 6 cycles) with CC-486 (5-azacitidine) at 300mg/day by oral intake on days 1-10, romidepsin at 12mg/m2 by IV infusion on Day 1 and 10 and dexamethasone at 40mg by oral intake on days 1 and 10 of each cycle
intervention type: Drug
intervention name: Romidepsin
description: Romidepsin (12mg/ m2 ) will be administered on days 1 and 10 of each cycle through a peripheral or central intravenous catheter for 6 cycles.
arm group label: 1- Experimental Treatment: Dose Escalation
arm group label: 2 - Experimental Treatment: Dose Expansion
intervention type: Drug
intervention name: Lenalidomide
description: Lenalidomide will be administered by oral intake in a dose-escalation with a starting dose of 5mg daily, a second dose level of 10mg daily, a third dose level at 15mg daily, and a fourth dose level at 20mg daily on days -7 to day 10 of first cycle. After the second cycle, lenalidomide will be given from day 1 to day 10 in each cycle for up to 6 cycles.
arm group label: 1- Experimental Treatment: Dose Escalation
arm group label: 2 - Experimental Treatment: Dose Expansion
intervention type: Drug
intervention name: CC-486 (5-azacitidine)
description: CC-486 (5-azacitidine) with a dose of 300mg oral intake daily will be given on day 1 to day 10 for 6 cycles.
arm group label: 1- Experimental Treatment: Dose Escalation
arm group label: 2 - Experimental Treatment: Dose Expansion
intervention type: Drug
intervention name: Dexamethasone
description: Dexamethasone, 40mg, PO, will be given on days 1 and 10 of each cycle.
arm group label: 1- Experimental Treatment: Dose Escalation
arm group label: 2 - Experimental Treatment: Dose Expansion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark J Roschewski, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
last name: NCI Medical Oncology Referral Office
phone: (240) 760-6050
email: ncimo_referrals@nih.gov
last name: Mark J Roschewski, M.D.
phone: (240) 760-6183
email: mark.roschewski@nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2020-C-0127.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Neoplasms
mesh term: Lymphoma, T-Cell
mesh term: Lymphoma, T-Cell, Peripheral
mesh term: Lymphoma, T-Cell, Cutaneous
mesh term: Dexamethasone
mesh term: Lenalidomide
mesh term: Azacitidine
mesh term: Romidepsin
mesh term: Cc-486
sharing ipd: Yes
ipd description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data will be available during the study and indefinitely. @@@@@@Genomic data will be available once genomic data are uploaded per protocol GDS plan for as long as database is active
ipd access criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data will be made available via dbGaP through requests to the data custodians.