<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/NCT04447716</url>
  </required_header>
  <id_info>
    <org_study_id>19P.835</org_study_id>
    <nct_id>NCT04447716</nct_id>
  </id_info>
  <brief_title>An Early Phase Study of Venetoclax, Lenalidomide, and Rituximab/Hyaluronidase in Slow-Growing Lymphomas That Have Come Back After Treatment or Have Not Responded to Treatment</brief_title>
  <official_title>A Phase I Study of Venetoclax + Lenalidomide + Rituximab Hyaluronidase in Relapsed or Refractory (R/R) Indolent Non-Hodgkin's Lymphoma (iNHL).</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thomas Jefferson University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Thomas Jefferson University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of venetoclax when given together&#xD;
      with lenalidomide and rituximab hyaluronidase in treating patients with follicular lymphoma&#xD;
      and marginal zone lymphoma that has come back after treatment (relapsed) or has not responded&#xD;
      to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking the&#xD;
      action of a protein called Bcl-2, that helps cancer cells survive. Immunotherapy with&#xD;
      lenalidomide, may induce changes in body's immune system and may interfere with the ability&#xD;
      of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as&#xD;
      rituximab and rituximab hyaluronidase, may help the body's immune system attack the cancer,&#xD;
      and may interfere with the ability of tumor cells to grow and spread. The purpose of this&#xD;
      research is to determine if the combination of three drugs, venetoclax, lenalidomide, and&#xD;
      rituximab hyaluronidase are safe to administer in patients whose low-grade lymphoma&#xD;
      (follicular or marginal zone) has come back after initial therapy or was not responsive to&#xD;
      initial therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the safety (and the recommended phase 2 dose [RP2D]), of the combination of&#xD;
      venetoclax, lenalidomide, and rituximab hyaluronidase in patients with relapsed/refractory&#xD;
      (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the overall response rate (ORR) with rituximab hyaluronidase, venetoclax, and&#xD;
      lenalidomide.&#xD;
&#xD;
      II. To determine the 2-year progression-free survival (PFS) with rituximab hyaluronidase,&#xD;
      venetoclax, and lenalidomide.&#xD;
&#xD;
      III. To determine the overall survival (OS) following therapy with rituximab hyaluronidase,&#xD;
      venetoclax, and lenalidomide.&#xD;
&#xD;
      CORRELATIVE STUDY OBJECTIVES:&#xD;
&#xD;
      I. Describe changes in the level of expression and expression ratio between anti-apoptotic&#xD;
      and pro-apoptotic BCL-2 family members before and after therapy with&#xD;
      venetoclax/lenalidomide/rituximab hyaluronidase for each patient.&#xD;
&#xD;
      II. Examine the metabolic landscape before and after venetoclax/lenalidomide/rituximab&#xD;
      hyaluronidase and their effects on mitochondrial metabolism.&#xD;
&#xD;
      III. Describe the immune effects of venetoclax and its effects on serum cytokines and&#xD;
      different immune cell subsets (e.g. B-cells, T-cells, dendritic cells, etc.) in addition to&#xD;
      T-cell activation markers and expression of immune checkpoint proteins.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of venetoclax.&#xD;
&#xD;
      Patient receive venetoclax orally (PO) once daily (QD) on days 1-28. Beginning cycle 2,&#xD;
      patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab&#xD;
      intravenously (IV) on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no&#xD;
      significant infusion reaction to rituximab) subcutaneously (SC) on day 1 of cycles 4, 6, 8,&#xD;
      10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1,&#xD;
      8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the&#xD;
      opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the&#xD;
      absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, and then for up to&#xD;
      5 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    pending protocol amendment for dose adjustment&#xD;
  </why_stopped>
  <start_date type="Actual">October 16, 2020</start_date>
  <completion_date type="Anticipated">March 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of dose-limiting toxicities</measure>
    <time_frame>During the first 56 days of therapy</time_frame>
    <description>Toxicity incidences assessed and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0, will be tabulated by patient cohort.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall response rate</measure>
    <time_frame>At the end of 12 month treatment period</time_frame>
    <description>Defined as the sum of the proportions of patients achieving a complete (CR) or partial response (PR) according to the Lugano Response Criteria. Analyses of efficacy outcomes will be descriptive. A 90% confidence interval will be computed for the best response rate (CR+PR rate) during the 12 month treatment period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Time from study registration to documented disease progression or death from any cause, assessed at 2 years</time_frame>
    <description>PFS distributions will be estimated using the Kaplan-Meier method, and the median PFS along with its corresponding 95% confidence interval will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Time from study registration to death from any cause, assessed at 2 years</time_frame>
    <description>OS distributions will be estimated using the Kaplan-Meier method, and the median OS along with its corresponding 95% confidence interval will be reported.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Level of expression and expression ratio between anti-apoptotic and pro-apoptotic BCL-2 family proteins measured by flow cytometry and messenger ribonucleic acid (mRNA)</measure>
    <time_frame>42 days of starting treatment through end of treatment</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Metabolic landscape</measure>
    <time_frame>42 days of screening through until end of treatment</time_frame>
    <description>Adenosine triphosphate (ATP) will be measured by mass spectroscopy and metabolic proteins will described by immunohistochemistry.</description>
  </other_outcome>
  <other_outcome>
    <measure>Immune profile</measure>
    <time_frame>42 days of starting treatment through until end of treatment</time_frame>
    <description>Flow cytometry will be used to measure T-cell and B-cell subsetswill be used to quantitate PD-1/PD-L1.</description>
  </other_outcome>
  <other_outcome>
    <measure>Immune profile</measure>
    <time_frame>42 days of starting treatment through until end of treatment</time_frame>
    <description>Immunohistochemistry will be used to quantitate PD-1/PD-L1.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Recurrent B-Cell Non-Hodgkin Lymphoma</condition>
  <condition>Recurrent Follicular Lymphoma</condition>
  <condition>Recurrent Indolent Adult Non-Hodgkin Lymphoma</condition>
  <condition>Recurrent Marginal Zone Lymphoma</condition>
  <condition>Refractory B-Cell Non-Hodgkin Lymphoma</condition>
  <condition>Refractory Follicular Lymphoma</condition>
  <condition>Refractory Indolent Adult Non-Hodgkin Lymphoma</condition>
  <condition>Refractory Marginal Zone Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient receive venetoclax PO QD on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab IV on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no significant infusion reaction to rituximab) SC on day 1 of cycles 4, 6, 8, 10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1, 8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Venetoclax</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)</arm_group_label>
    <other_name>1257044-40-8,</other_name>
    <other_name>4-(4-((2-(4-Chlorophenyl)-4</other_name>
    <other_name>4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide,</other_name>
    <other_name>ABT-0199,</other_name>
    <other_name>ABT-199,</other_name>
    <other_name>ABT199,</other_name>
    <other_name>RG7601,</other_name>
    <other_name>GDC-0199,</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)</arm_group_label>
    <other_name>191732-72-6,</other_name>
    <other_name>3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione,</other_name>
    <other_name>703813,</other_name>
    <other_name>CC-5013</other_name>
    <other_name>Revlimid</other_name>
    <other_name>CC5013</other_name>
    <other_name>CDC 501,</other_name>
    <other_name>lenalidomide,</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)</arm_group_label>
    <other_name>174722-31-7,</other_name>
    <other_name>687451,</other_name>
    <other_name>ABP 798,</other_name>
    <other_name>BI 695500,</other_name>
    <other_name>C2B8 Monoclonal Antibody,</other_name>
    <other_name>Chimeric Anti-CD20 Antibody,</other_name>
    <other_name>CT-P10,</other_name>
    <other_name>IDEC-102,</other_name>
    <other_name>IDEC-C2B8</other_name>
    <other_name>IDEC-C2B8 Monoclonal Antibody,</other_name>
    <other_name>MabThera,</other_name>
    <other_name>Monoclonal Antibody IDEC-C2B8,</other_name>
    <other_name>PF-05280586,</other_name>
    <other_name>Rituxan,</other_name>
    <other_name>Rituximab,</other_name>
    <other_name>RITUX</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab and Hyaluronidase Human</intervention_name>
    <description>Given SC</description>
    <arm_group_label>Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)</arm_group_label>
    <other_name>Rituxan Hycela,</other_name>
    <other_name>Rituximab Plus Hyaluronidase,</other_name>
    <other_name>Rituximab/Hyaluronidase,</other_name>
    <other_name>Rituximab/Hyaluronidase Human</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Signed informed consent form&#xD;
&#xD;
          -  Ability and willingness to comply with the requirements of the study protocol&#xD;
&#xD;
          -  Able to swallow oral medications whole&#xD;
&#xD;
          -  Patients must have received at least one prior systemic therapy&#xD;
&#xD;
          -  Histologically confirmed indolent B-cell non-Hodgkin's lymphoma (NHL) of any of the&#xD;
             following subtypes recognized by the World Health Organization (WHO) classification:&#xD;
             Follicular lymphoma and marginal zone lymphoma. Patients with indolent non-Hodgkin's&#xD;
             Lymphoma (iNHL) should have received at least 1 previous prior therapy&#xD;
&#xD;
          -  Patients must have an indication for treatment by Groupe d'Etude des Lymphomes&#xD;
             Folliculaires (GELF) criteria in the opinion of the investigator&#xD;
&#xD;
          -  Radiographically measurable disease by computed tomography (CT) scan, defined as at&#xD;
             least one node &gt; 1.5 cm in size&#xD;
&#xD;
          -  All study participants must be registered into the mandatory lenalidomide risk&#xD;
             evaluation and mitigation strategy (REMS) program, and be willing and able to comply&#xD;
             with the requirements of the REMS program&#xD;
&#xD;
          -  Females of reproductive potential must adhere to the scheduled pregnancy testing as&#xD;
             required in the lenalidomide REMS program&#xD;
&#xD;
          -  Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. Patients&#xD;
             intolerant to aspirin (ASA) may use low molecular weight heparin or equivalent.&#xD;
             Inability to take any form of prophylaxis excludes participation&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status of 0, 1, or 2&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL (unless caused by underlying disease, as established by extensive&#xD;
             bone marrow involvement or as a result of hypersplenism secondary to the involvement&#xD;
             of the spleen by lymphoma per the investigator)&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1.0 x 10^9/L (unless caused by underlying disease, as&#xD;
             established by extensive bone marrow involvement or as a result of hypersplenism&#xD;
             secondary to the involvement of the spleen by lymphoma per the investigator)&#xD;
&#xD;
          -  Platelet count &gt;= 75 x 10^9/L (unless caused by underlying disease, as established by&#xD;
             extensive bone marrow involvement or as a result of hypersplenism secondary to the&#xD;
             involvement of the spleen by lymphoma per the investigator)&#xD;
&#xD;
          -  International normalized ratio &gt; 1.5 x upper limit of normal (ULN) for patients not&#xD;
             receiving therapeutic anticoagulation&#xD;
&#xD;
          -  Partial thromboplastin time (PTT) or activated PTT (aPTT) =&lt; 1.5 x ULN&#xD;
&#xD;
          -  Creatinine clearance &gt;= 60 mL/min, calculated with the use of the 24-hour creatinine&#xD;
             clearance or modified Cockcroft-Gault equation&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =&lt; 2.5 x ULN&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x ULN (or =&lt; 3 x ULN for patients with documented Gilbert&#xD;
             syndrome)&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             result within 14 days prior to registration&#xD;
&#xD;
          -  For women of childbearing potential: agreement to remain abstinent (refrain from&#xD;
             heterosexual intercourse) or use a contraceptive method with a failure rate of &lt; 1%&#xD;
             per year during the treatment period and for at least 30 days after the last dose of&#xD;
             venetoclax and lenalidomide or 12 months after the last dose of rituximab, whichever&#xD;
             is longer * Women must refrain from donating eggs during this same period&#xD;
&#xD;
             * A woman is considered to be of childbearing potential if she is postmenarcheal, has&#xD;
             not reached a postmenopausal state (&gt;= 12 continuous months of amenorrhea with no&#xD;
             identified cause other than menopause), and has not undergone surgical sterilization&#xD;
             (removal of ovaries and/or uterus) * Examples of contraceptive methods with a failure&#xD;
             rate of &lt; 1% per year include bilateral tubal ligation, male sterilization, hormonal&#xD;
             contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and&#xD;
             copper intrauterine devices * The reliability of sexual abstinence should be evaluated&#xD;
             in relation to the duration of the clinical trial and the preferred and usual&#xD;
             lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,&#xD;
             symptothermal, or postovulation methods) and withdrawal are not acceptable methods of&#xD;
             contraception&#xD;
&#xD;
          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use&#xD;
             contraceptive measures, and agreement to refrain from donating sperm, as defined&#xD;
             below: * With female partners of childbearing potential, men must remain abstinent or&#xD;
             use a condom plus an additional contraceptive method that together result in a failure&#xD;
             rate of &lt; 1% per year during the treatment period and for at least 6 months after the&#xD;
             last dose of rituximab and for at least 30 days after the last dose of venetoclax and&#xD;
             lenalidomide whichever is longer. Men must refrain from donating sperm during this&#xD;
             same period * With pregnant female partners, men must remain abstinent or use a condom&#xD;
             during the treatment period and for at least 6 months after the last dose of rituximab&#xD;
             to avoid exposing the embryo * The reliability of sexual abstinence should be&#xD;
             evaluated in relation to the duration of the clinical trial and the preferred and&#xD;
             usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,&#xD;
             symptothermal, or postovulation methods) and withdrawal are not acceptable methods of&#xD;
             contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Known hypersensitivity to any of the study drugs study drugs&#xD;
&#xD;
          -  Known central nervous system (CNS) involvement by lymphoma&#xD;
&#xD;
          -  Prior allogeneic stem cell transplant is not permitted if patient is fewer than 4&#xD;
             months from transplant and has either active graft versus host disease or on&#xD;
             immunosuppression&#xD;
&#xD;
          -  History of severe allergic reactions to humanized monoclonal antibodies&#xD;
&#xD;
          -  Prior use of lenalidomide or venetoclax or other BCL2 family inhibitors; prior&#xD;
             rituximab is allowed as long as they continue to express CD20 and are not rituximab&#xD;
             refractory as defined as: * Did not respond (at least a partial response [PR]) to&#xD;
             rituximab or rituximab (R)-chemoregimen therapy * Time to disease progression &lt; 6&#xD;
             months after last rituximab dose&#xD;
&#xD;
          -  History of other malignancy that could affect compliance with the protocol or&#xD;
             interpretation of results * Patients with a history of curatively treated basal or&#xD;
             squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the&#xD;
             cervix are eligible * Patients with a malignancy that has been treated with surgery&#xD;
             alone with curative intent will also be excluded. Individuals in documented remission&#xD;
             without treatment for &gt;= 2 years prior to enrollment may be included at the discretion&#xD;
             of the investigator&#xD;
&#xD;
          -  Evidence of significant, uncontrolled concomitant diseases that could affect&#xD;
             compliance with the protocol or interpretation of results or that could increase risk&#xD;
             to the patient, including renal disease that would preclude chemotherapy&#xD;
             administration or pulmonary disease (including obstructive pulmonary disease and&#xD;
             history of bronchospasm)&#xD;
&#xD;
          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection&#xD;
             (excluding fungal infections of nail beds) at study enrollment, or any major episode&#xD;
             of infection requiring treatment with IV antibiotics or hospitalization (relating to&#xD;
             the completion of the course of antibiotics) within 4 weeks prior to registration&#xD;
&#xD;
          -  Requires the use of warfarin (because of potential drug-drug interactions that may&#xD;
             potentially increase the exposure of warfarin)&#xD;
&#xD;
          -  Received the following agents within 7 days prior to registration: * Steroid therapy&#xD;
             for anti-neoplastic intent * Strong and moderate CYP3A inhibitors * Strong and&#xD;
             moderate CYP3A inducers * Consumed grapefruit, grapefruit products, Seville oranges&#xD;
             (including marmalade containing Seville oranges), or star fruit within 3 days prior to&#xD;
             the first dose of venetoclax&#xD;
&#xD;
          -  Clinically significant history of liver disease, including viral or other hepatitis,&#xD;
             current alcohol abuse, or cirrhosis Presence of positive test results for hepatitis B&#xD;
             virus (HBV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody *&#xD;
             Patients who are positive for HCV antibody must be negative for HCV by polymerase&#xD;
             chain reaction (PCR) to be eligible for study participation * Patients with occult or&#xD;
             prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and&#xD;
             negative HBsAg) may be included if HBV deoxyribonucleic acid (DNA) is undetectable.&#xD;
             These patients must be willing to undergo monthly DNA testing.&#xD;
&#xD;
          -  Known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus&#xD;
             1 (HTLV-1)&#xD;
&#xD;
          -  Receipt of live-virus vaccines within 28 days prior to the initiation of study&#xD;
             treatment or need for live-virus vaccines at any time during study treatment&#xD;
&#xD;
          -  Pregnant or lactating, or intending to become pregnant during the study&#xD;
&#xD;
          -  Recent major surgery (within 6 weeks prior to the start of cycle 1, day 1) other than&#xD;
             for diagnosis&#xD;
&#xD;
          -  Malabsorption syndrome or other condition that precludes enteral route of&#xD;
             administration&#xD;
&#xD;
          -  Known allergy to both xanthine oxidase inhibitors and rasburicase&#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>Ubaldo R Martinez-Outschoorn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Thomas Jefferson University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sidney Kimmel Cancer Center at Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>April 9, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Follicular</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Lymphoma, B-Cell, Marginal Zone</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
    <mesh_term>Lenalidomide</mesh_term>
    <mesh_term>Venetoclax</mesh_term>
    <mesh_term>Piperidine</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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/NCT04447716
org study id: 19P.835
nct id: NCT04447716
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects and best dose of venetoclax when given together
      with lenalidomide and rituximab hyaluronidase in treating patients with follicular lymphoma
      and marginal zone lymphoma that has come back after treatment (relapsed) or has not responded
      to treatment (refractory). Venetoclax may stop the growth of cancer cells by blocking the
      action of a protein called Bcl-2, that helps cancer cells survive. Immunotherapy with
      lenalidomide, may induce changes in body's immune system and may interfere with the ability
      of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as
      rituximab and rituximab hyaluronidase, may help the body's immune system attack the cancer,
      and may interfere with the ability of tumor cells to grow and spread. The purpose of this
      research is to determine if the combination of three drugs, venetoclax, lenalidomide, and
      rituximab hyaluronidase are safe to administer in patients whose low-grade lymphoma
      (follicular or marginal zone) has come back after initial therapy or was not responsive to
      initial therapy.
PRIMARY OBJECTIVE:

      I. To determine the safety (and the recommended phase 2 dose [RP2D]), of the combination of
      venetoclax, lenalidomide, and rituximab hyaluronidase in patients with relapsed/refractory
      (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL).

      SECONDARY OBJECTIVES:

      I. To determine the overall response rate (ORR) with rituximab hyaluronidase, venetoclax, and
      lenalidomide.

      II. To determine the 2-year progression-free survival (PFS) with rituximab hyaluronidase,
      venetoclax, and lenalidomide.

      III. To determine the overall survival (OS) following therapy with rituximab hyaluronidase,
      venetoclax, and lenalidomide.

      CORRELATIVE STUDY OBJECTIVES:

      I. Describe changes in the level of expression and expression ratio between anti-apoptotic
      and pro-apoptotic BCL-2 family members before and after therapy with
      venetoclax/lenalidomide/rituximab hyaluronidase for each patient.

      II. Examine the metabolic landscape before and after venetoclax/lenalidomide/rituximab
      hyaluronidase and their effects on mitochondrial metabolism.

      III. Describe the immune effects of venetoclax and its effects on serum cytokines and
      different immune cell subsets (e.g. B-cells, T-cells, dendritic cells, etc.) in addition to
      T-cell activation markers and expression of immune checkpoint proteins.

      OUTLINE: This is a dose-escalation study of venetoclax.

      Patient receive venetoclax orally (PO) once daily (QD) on days 1-28. Beginning cycle 2,
      patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab
      intravenously (IV) on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no
      significant infusion reaction to rituximab) subcutaneously (SC) on day 1 of cycles 4, 6, 8,
      10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1,
      8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the
      opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, and then for up to
      5 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of dose-limiting toxicities
time frame: During the first 56 days of therapy
description: Toxicity incidences assessed and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0, will be tabulated by patient cohort.
measure: Overall response rate
time frame: At the end of 12 month treatment period
description: Defined as the sum of the proportions of patients achieving a complete (CR) or partial response (PR) according to the Lugano Response Criteria. Analyses of efficacy outcomes will be descriptive. A 90% confidence interval will be computed for the best response rate (CR+PR rate) during the 12 month treatment period.
measure: Progression-free survival (PFS)
time frame: Time from study registration to documented disease progression or death from any cause, assessed at 2 years
description: PFS distributions will be estimated using the Kaplan-Meier method, and the median PFS along with its corresponding 95% confidence interval will be reported.
measure: Overall survival (OS)
time frame: Time from study registration to death from any cause, assessed at 2 years
description: OS distributions will be estimated using the Kaplan-Meier method, and the median OS along with its corresponding 95% confidence interval will be reported.
measure: Level of expression and expression ratio between anti-apoptotic and pro-apoptotic BCL-2 family proteins measured by flow cytometry and messenger ribonucleic acid (mRNA)
time frame: 42 days of starting treatment through end of treatment
measure: Metabolic landscape
time frame: 42 days of screening through until end of treatment
description: Adenosine triphosphate (ATP) will be measured by mass spectroscopy and metabolic proteins will described by immunohistochemistry.
measure: Immune profile
time frame: 42 days of starting treatment through until end of treatment
description: Flow cytometry will be used to measure T-cell and B-cell subsetswill be used to quantitate PD-1/PD-L1.
measure: Immune profile
time frame: 42 days of starting treatment through until end of treatment
description: Immunohistochemistry will be used to quantitate PD-1/PD-L1.
arm group label: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)
arm group type: Experimental
description: Patient receive venetoclax PO QD on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21. Patients also receive rituximab IV on days 1, 8, 15, and 22 of cycle 2 and rituximab hyaluronidase (if no significant infusion reaction to rituximab) SC on day 1 of cycles 4, 6, 8, 10, and 12. Patients may receive rituximab IV (instead of rituximab hyaluronidase) on days 1, 8, 15, and 22 of cycles 4, 6, 8, 10, and 12 if the patient requires rituximab IV in the opinion of the treating physician. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Venetoclax
description: Given PO
arm group label: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)
other name: 1257044-40-8,
other name: 4-(4-((2-(4-Chlorophenyl)-4
other name: 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide,
other name: ABT-0199,
other name: ABT-199,
other name: ABT199,
other name: RG7601,
other name: GDC-0199,
intervention type: Drug
intervention name: Lenalidomide
description: Given PO
arm group label: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)
other name: 191732-72-6,
other name: 3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione,
other name: 703813,
other name: CC-5013
other name: Revlimid
other name: CC5013
other name: CDC 501,
other name: lenalidomide,
intervention type: Biological
intervention name: Rituximab
description: Given IV
arm group label: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)
other name: 174722-31-7,
other name: 687451,
other name: ABP 798,
other name: BI 695500,
other name: C2B8 Monoclonal Antibody,
other name: Chimeric Anti-CD20 Antibody,
other name: CT-P10,
other name: IDEC-102,
other name: IDEC-C2B8
other name: IDEC-C2B8 Monoclonal Antibody,
other name: MabThera,
other name: Monoclonal Antibody IDEC-C2B8,
other name: PF-05280586,
other name: Rituxan,
other name: Rituximab,
other name: RITUX
intervention type: Biological
intervention name: Rituximab and Hyaluronidase Human
description: Given SC
arm group label: Treatment (venetoclax, lenalidomide, rituximab, hyaluronidase)
other name: Rituxan Hycela,
other name: Rituximab Plus Hyaluronidase,
other name: Rituximab/Hyaluronidase,
other name: Rituximab/Hyaluronidase Human
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ubaldo R Martinez-Outschoorn, MD
role: Principal Investigator
affiliation: Thomas Jefferson University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Follicular
mesh term: Lymphoma, Non-Hodgkin
mesh term: Lymphoma, B-Cell, Marginal Zone
mesh term: Lymphoma, B-Cell
mesh term: Recurrence
mesh term: Rituximab
mesh term: Antineoplastic Agents, Immunological
mesh term: Lenalidomide
mesh term: Venetoclax
mesh term: Piperidine
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal