<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/NCT04479267</url>
  </required_header>
  <id_info>
    <org_study_id>2019-135</org_study_id>
    <secondary_id>P30CA022453</secondary_id>
    <nct_id>NCT04479267</nct_id>
  </id_info>
  <brief_title>Polatuzumab Vedotin and Combination Chemotherapy for the Treatment of Previously Untreated Lymphoma</brief_title>
  <official_title>A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in Combination With Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients With Previously Untreated Double and Triple Hit Lymphoma, Double Expressor Lymphoma and High-Grade B Cell Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Barbara Ann Karmanos Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Barbara Ann Karmanos Cancer Institute</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well polatuzumab vedotin and combination chemotherapy work in&#xD;
      treating patients with previously untreated double, triple hit lymphoma, Double Expressor&#xD;
      Lymphoma or High-Grade B Cell Lymphoma. Polatuzumab vedotin is a monoclonal antibody that&#xD;
      works by binding with cancer cells and releasing another chemotherapy drug, called monomethyl&#xD;
      auristatin E, into the cell causing the cancer cells to die or stop growing. Chemotherapy&#xD;
      drugs, such as rituximab, cyclophosphamide, doxorubicin, and prednisone, work in different&#xD;
      ways to stop the growth of cancer cells, either by killing the cells, by stopping them from&#xD;
      dividing, or by stopping them from spreading. Giving polatuzumab vedotin with combination&#xD;
      chemotherapy may work better in treating patients with double or triple hit lymphoma compared&#xD;
      to combination chemotherapy alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the rate of complete remission (CR) with polatuzumab vedotin plus rituximab,&#xD;
      cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) in patients with newly&#xD;
      diagnosed previously untreated double, triple hit lymphoma, Double Expressor Lymphoma or&#xD;
      High-Grade B Cell Lymphoma. as measured by positron emission tomography (PET)-defined CR rate&#xD;
      using the modified Lugano response criteria at the time of primary response assessment (6-8&#xD;
      weeks after cycle 6 day 1 or last dose of study medication).&#xD;
&#xD;
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the rate of complete remission (CR) with polatuzumab vedotin plus rituximab,&#xD;
      cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) in patients with newly&#xD;
      diagnosed previously untreated double, triple hit lymphoma, Double Expressor Lymphoma or&#xD;
      High-Grade B Cell Lymphoma. as measured by positron emission tomography (PET)-defined CR rate&#xD;
      using the modified Lugano response criteria at the time of primary response assessment (6-8&#xD;
      weeks after cycle 6 day 1 or last dose of study medication).&#xD;
&#xD;
      SECONDARY SAFETY OBJECTIVE:&#xD;
&#xD;
      I. To evaluate the safety and tolerability of the combination of polatuzumab vedotin (PoV)&#xD;
      plus R-CHP as defined by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.&#xD;
&#xD;
      SECONDARY EFFICACY OBJECTIVES:&#xD;
&#xD;
      I. To assess the progression free survival (PFS) with PoV plus R-CHP in the above-mentioned&#xD;
      patient population.&#xD;
&#xD;
      II. To assess the overall survival (OS) with PoV plus R-CHP in the above-mentioned patient&#xD;
      population.&#xD;
&#xD;
      III. To assess the overall response rate (ORR; complete response [CR] or partial response&#xD;
      [PR]) at the time of primary response assessment, based on modified Lugano PET-computed&#xD;
      tomography (CT) criteria, as determined by the investigator.&#xD;
&#xD;
      IV. To assess the duration of response (DOR) to PoV plus R-CHP based on PET-CT, as determined&#xD;
      by the investigators in the above-mentioned patient population.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To explore the relationship between CD79b expression and response to treatment with PoV&#xD;
      plus R-CHP.&#xD;
&#xD;
      II. To explore the relationship between MYC expression and response to treatment with PoV&#xD;
      plus R-CHP.&#xD;
&#xD;
      III. To explore polatuzumab vedotin treatment on Myc protein expression.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive prednisone orally (PO), prednisolone intravenously (IV), or&#xD;
      methylprednisolone IV on days 1-5. Patients also receive rituximab IV, polatuzumab vedotin IV&#xD;
      over 30-90 minutes, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1. Treatment&#xD;
      repeats every 21 days for up to 6 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months for 12 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 21, 2020</start_date>
  <completion_date type="Anticipated">November 15, 2023</completion_date>
  <primary_completion_date type="Anticipated">November 15, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of complete remission</measure>
    <time_frame>Up to 6-8 weeks after cycle 6 day 1 (cycles = 21 days) or last dose of study medication</time_frame>
    <description>Will be assessed by modified Lugano response criteria for malignant lymphoma. The complete remission rate will be summarized by a binomial response rate and its associated 2-sided 80% confidence interval (CI) using Pearson-Klopper method. The primary efficacy analysis will be also performed based on all response evaluable subjects as a sensitivity analysis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 30 days after last dose of study treatment</time_frame>
    <description>Safety will be assessed through summaries of adverse events, summaries of changes from screening assessments in laboratory test results, electrocardiograms, and changes in vital signs. All adverse events occurring on or after first study treatment will be summarized by mapped term, appropriate thesaurus levels, and National Cancer Institute (NCI) Common Terminology Criteria Adverse Events version (v) 4.03 toxicity grade. All serious adverse events will be listed separately and summarized. Deaths reported during the study treatment period and those reported during follow-up after treatment discontinuation will be listed. Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, pulse oximetry, and blood pressure) data will be displayed by time, with NCI Common Terminology Criteria for Adverse Events v5.0. Grade 3 and 4 values identified where appropriate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>From the start date of the treatment until the date of progression or death from any cause, whichever occurs first, assessed up to 12 months</time_frame>
    <description>The distribution of PFS will be graphically summarized using the Kaplan-Meier (KM) curve and the median PFS and its associated 2-sided CI will be estimated using the KM estimator. The median follow-up time and its 2-sided CI will be estimated using the reverse KM estimator.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (ORR)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Will be defined as complete response (CR) or partial response (PR) at primary response assessment based on positron emission tomography/computed tomography as determined by the investigator and assessed using modified Lugano response criteria. CR and PR will be summarized using frequency and percentage. The ORR will be summarized by a binomial response rate and its associated 2-sided CI using Pearson-Klopper method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>From the date of CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is documented among all treated subjects who had a confirmed CR or PR, assessed up to 12 months</time_frame>
    <description>The distribution of DOR will be graphically summarized using the KM curve and the median PFS and its associated 2-sided CI will be estimated using the KM estimator.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Biomarker assessment</measure>
    <time_frame>Up to time of disease progression, assessed up to 12 months</time_frame>
    <description>Exploratory analyses of biomarkers related to tumor biology and the mechanisms of action of polatuzumab vedotin and rituximab will be conducted. Analyses will assess prognostic and/or predictive value of candidate biomarkers separately for each histological subtype and both investigator and Independent Review Committee assessed outcomes. Specifically, the association between candidate biomarkers and positron emission tomography (PET)-computed tomography (CT) CR rate and objective response rate and potentially other measures of efficacy and safety, independent of treatment, will be explored to assess potential prognostic value. In addition, the potential effect modification of treatment effect on PET-CT CR rate and OR rate and potentially other measures of efficacy and safety, by biomarker status, will be explored to assess potential predictive value.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">49</enrollment>
  <condition>Diffuse Large B-Cell Lymphoma</condition>
  <condition>High Grade B-Cell Lymphoma w/MYC &amp; BCL2 or BCL6 Rearrangements</condition>
  <condition>High Grade B-Cell Lymphoma w/MYC, BCL2 &amp; BCL6 Rearrangements</condition>
  <condition>Double Expressor Lymphoma</condition>
  <condition>High-grade B-cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive prednisone PO, prednisolone IV, or methylprednisolone IV on days 1-5. Patients also receive rituximab IV, polatuzumab vedotin IV over 30-90 minutes, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>.delta.1-Cortisone, 1, 2-Dehydrocortisone, 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione, 53-03-2, Adasone, Cortancyl, Dacortin, , Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>(11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, 1,2-Dehydrohydrocortisone, 50-24-8, 9120, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylprednisolone</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>(6alpha,11beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,20-dione, 6Alpha-Methylprednisolone, Adlone, Caberdelta M, DepMedalone, Depo Moderin, Depo-Nisolone, Duralone, Emmetipi, Esametone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>174722-31-7, 687451, ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Polatuzumab Vedotin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>1313206-42-6, ADC DCDS4501A, Antibody-Drug Conjugate DCDS4501A, DCDS4501A, FCU 2711, POLATUZUMAB VEDOTIN, polatuzumab vedotin-piiq, Polivy, RG7596, Ro 5541077-000</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>1-bis(2-chloroethyl)-amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxorubicin Hydrochloride</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (polatuzumab vedotin, R-CHP)</arm_group_label>
    <other_name>14-Hydroxydaunorubicin Hydrochloride, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent form (ICF)&#xD;
&#xD;
          -  Previously untreated patients (except for one prior cycle of CHOP+R) with diffuse&#xD;
             large B-cell lymphoma (DLBCL) as determined by local pathology. World Health&#xD;
             Organization (WHO) histologies will include:&#xD;
&#xD;
               -  Double hit lymphoma (DHL) or triple hit lymphoma (THL) confirmed by fluorescence&#xD;
                  in situ hybridization (FISH) testing by local pathology (defined as MYC and BCL2&#xD;
                  and/or BCL6 rearrangements)&#xD;
&#xD;
               -  High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements&#xD;
&#xD;
               -  Double expressor lymphoma (DEL) defined as overexpression of MYC(&gt; or = to 40%)&#xD;
                  and BCL2 (&gt; or = to 50%) identified by immunohistochemistry (IHC)&#xD;
&#xD;
               -  High grade B-cell lymphoma (HGBL) NOS subtype&#xD;
&#xD;
          -  Availability of archival formalin-fixed paraffin-embedded (FFPE) tissue blocks or 15&#xD;
             unstained slides serial sections (3-5 um in thickness) prior to study enrollment. The&#xD;
             pathology report must be available for review and a tissue block sent for&#xD;
             retrospective central confirmation of diagnosis. If central confirmation is unable to&#xD;
             be performed on submitted material, stained slides used for diagnosis and/or&#xD;
             additional tumor tissue specimens may also be requested&#xD;
&#xD;
             * For clarification: Only availability of tumor sample must be verified prior to C1D1&#xD;
             however treatment can commence prior to completion of central review. The adequacy of&#xD;
             the tissue will be confirmed if possible (ie. if it will not delay treatment).&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2&#xD;
&#xD;
          -  Life expectancy of at least 24 weeks&#xD;
&#xD;
          -  At least one bi-dimensionally measurable lesion &gt; 1.5 cm in its longest dimension as&#xD;
             measured by CT or magnetic resonance imaging (MRI)&#xD;
&#xD;
          -  Ability and willingness to comply with the study protocol procedures&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &gt;= 45% on cardiac multiple-gated acquisition&#xD;
             (MUGA) scan or cardiac echocardiogram (ECHO)&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.0 g/dL without packed RBC transfusion during 14 days before first&#xD;
             treatment (unless due to underlying disease, as established by extensive bone marrow&#xD;
             involvement or due to hypersplenism secondary to the involvement of the spleen by&#xD;
             DLBCL per the investigator)&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,000/uL (unless due to underlying disease, as&#xD;
             established by extensive bone marrow involvement or due to hypersplenism secondary to&#xD;
             the involvement of the spleen by DLBCL per the investigator)&#xD;
&#xD;
          -  Platelet count &gt;= 75,000/uL (unless due to underlying disease, as established by&#xD;
             extensive bone marrow involvement or due to hypersplenism secondary to the involvement&#xD;
             of the spleen by DLBCL per the investigator)&#xD;
&#xD;
          -  For women of childbearing potential: agreement to remain abstinent (refrain from&#xD;
             heterosexual intercourse) or use contraceptive methods that result in a failure rate&#xD;
             of &lt; 1% per year during the treatment period and for at least 12 months after the last&#xD;
             dose of study treatment&#xD;
&#xD;
               -  A woman is considered to be of childbearing potential if she is post-menarcheal,&#xD;
                  has not reached a postmenopausal state (&gt;= 12 continuous months of amenorrhea&#xD;
                  with no identified cause other than menopause), and has not undergone surgical&#xD;
                  sterilization (removal of ovaries and/or uterus)&#xD;
&#xD;
               -  Examples of contraceptive methods with a failure rate of &lt; 1% per year include&#xD;
                  bilateral tubal ligation, male sterilization, hormonal contraceptives that&#xD;
                  inhibit ovulation, hormone-releasing intrauterine devices, and copper&#xD;
                  intrauterine devices&#xD;
&#xD;
               -  Women must refrain from donating eggs during the same period&#xD;
&#xD;
               -  The reliability of sexual abstinence should be evaluated in relation to the&#xD;
                  duration of the clinical trial and the preferred and usual lifestyle of the&#xD;
                  patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or&#xD;
                  post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
                  contraception&#xD;
&#xD;
          -  For women of childbearing potential, a negative serum pregnancy test result within 7&#xD;
             days prior to commencement of dosing. Women who are considered not to be of&#xD;
             childbearing potential are not required to have a pregnancy test&#xD;
&#xD;
          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use&#xD;
             a condom, and agreement to refrain from donating sperm, as defined below:&#xD;
&#xD;
             * With female partners of childbearing potential or pregnant female partners, men must&#xD;
             remain abstinent or use a condom during the treatment period and for at least 5 months&#xD;
             after the last dose of polatuzumab vedotin, 3 months after the last dose of rituximab,&#xD;
             and for at least 6 months after the last dose of cyclophosphamide to avoid exposing&#xD;
             the embryo for the duration of the pregnancy. Men must refrain from donating sperm&#xD;
             during this same period&#xD;
&#xD;
          -  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation&#xD;
             methods) and withdrawal are not acceptable methods of contraception. Male patients&#xD;
             considering preservation of fertility should bank sperm before study treatment&#xD;
&#xD;
          -  CRITERIA FOR TISSUE SUBMISSION:&#xD;
&#xD;
          -  Eligible patients must have available at the study site a representative&#xD;
             formalin-fixed, paraffin-embedded tumor specimen that enabled the definitive diagnosis&#xD;
             of DLBCL&#xD;
&#xD;
               -  The specimen must contain adequate evaluable tumor cells (&gt;= 20% for excisional&#xD;
                  biopsy and &gt;= 50% if sample is a core biopsy) to enable relevant biomarker&#xD;
                  analysis&#xD;
&#xD;
               -  A tissue block (preferred) or 15 serial, freshly cut, unstained slides plus punch&#xD;
                  biopsy of the tissue block accompanied by an associated pathology report will be&#xD;
                  requested. Punch biopsy is required only with the slide submission. Cytological&#xD;
                  or fine-needle aspiration samples are not acceptable&#xD;
&#xD;
               -  If the archival tissue is unavailable or insufficient on the basis of the above&#xD;
                  criteria, the patient may still be eligible if the patient is willing to provide&#xD;
                  tissue from a pretreatment core or excisional/incisional biopsy of the tumor.&#xD;
                  Cytological or fine-needle aspiration samples are not acceptable. The sample&#xD;
                  should be shipped according to instructions provided in the laboratory manual.&#xD;
                  Tissue collected on study will not be returned to sites. If needed, additional&#xD;
                  slides from previously collected samples may be requested. Cases received from&#xD;
                  each of the participating institutes should be histological confirmed according&#xD;
                  to the 2016 WHO classification of tumors of hematopoietic and lymphoid neoplasm.&#xD;
                  The evaluation process by immunohistochemistry (IHC) and fluorescent in situ&#xD;
                  hybridization (FISH) requires the possession of representative amount of tissues&#xD;
                  in a paraffin embedded block to be sent to the primary testing institution&#xD;
                  (Karmanos Cancer Center, Detroit, Michigan). Shipped slides should be placed in&#xD;
                  proper containers to avoid breakage during shipping. Blocks of paraffin embedded&#xD;
                  tissue or slides should be sent with a tracking number the address. In addition,&#xD;
                  the participation institution should call the laboratory at 313-576-8351 (Julie&#xD;
                  Boerner) for any sample that they ship and provide tracking number&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to any of the individual components of R-cyclophosphamide,&#xD;
             doxorubicin hydrochloride, oxaliplatin, prednisone (CHOP) or any component of PoV,&#xD;
             including prior receipt of anthracyclines or history of severe allergic or&#xD;
             anaphylactic reactions to humanized or murine monoclonal antibodies (MAbs) (or&#xD;
             recombinant antibody-related fusion proteins) or known sensitivity or allergy to&#xD;
             murine products&#xD;
&#xD;
          -  Contraindication to rituximab or prior administration of an anti CD 20 antibody&#xD;
&#xD;
          -  Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy,&#xD;
             or any investigational agent for the purposes of treating cancer prior to cycle 1 day&#xD;
             1 with the following exceptions:&#xD;
&#xD;
               -  One prior treatment cycle of CHOP+R is allowed. Patients who received one prior&#xD;
                  R-CHOP will receive 6 cycles of R-CHP plus Polatuzumab Vedotin per protocol&#xD;
                  treatment.&#xD;
&#xD;
               -  Glucocorticoid treatment required for lymphoma symptom control prior to the start&#xD;
                  of study treatment, prednisone 100 mg or equivalent can be given for a maximum of&#xD;
                  13 days as a prephase treatment, with all tumor assessments completed prior to&#xD;
                  starting prednisone&#xD;
&#xD;
               -  One dose of prophylactic intrathecal chemotherapy with methotrexate&#xD;
&#xD;
          -  Grade 3b follicular lymphoma&#xD;
&#xD;
          -  Primary mediastinal (thymic) large B-cell lymphoma&#xD;
&#xD;
          -  Burkitt lymphoma&#xD;
&#xD;
          -  Primary or secondary central nervous system (CNS) lymphoma (primary or secondary&#xD;
             involvement), primary effusion DLBCL, and primary cutaneous DLBCL&#xD;
&#xD;
          -  Current grade 2 peripheral neuropathy per Common Terminology Criteria for Adverse&#xD;
             Events (CTCAE) 5.0&#xD;
&#xD;
          -  History of other malignancy that could affect compliance with the protocol or&#xD;
             interpretation of results. Exceptions include, but are not limited to:&#xD;
&#xD;
               -  Patients with a history of curatively treated basal or squamous cell carcinoma of&#xD;
                  the skin, in situ carcinoma of the cervix or ductal carcinoma in situ of the&#xD;
                  breast at any time prior to the study are eligible&#xD;
&#xD;
               -  A patient with any other malignancy that has been treated with surgery alone with&#xD;
                  curative intent and the malignancy has been in remission without treatment for &gt;=&#xD;
                  3 years prior to enrollment is eligible&#xD;
&#xD;
               -  Patients with low-grade, early-stage prostate cancer with no requirement for&#xD;
                  therapy at any time prior to study are eligible&#xD;
&#xD;
          -  Evidence of significant, uncontrolled concomitant diseases that could affect&#xD;
             compliance with the protocol or interpretation of results, including significant&#xD;
             cardiovascular disease (such as New York Heart Association class III or IV cardiac&#xD;
             disease, myocardial infarction within the last 6 months, unstable arrhythmias, or&#xD;
             unstable angina) or significant pulmonary disease (including obstructive pulmonary&#xD;
             disease and history of bronchospasm)&#xD;
&#xD;
          -  History or presence of an abnormal electrocardiogram (ECG) that is clinically&#xD;
             significant in the investigator's opinion, including complete left bundle branch&#xD;
             block, second- or third-degree heart block&#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 of&#xD;
             infection requiring treatment with intravenous (IV) antibiotics or hospitalization&#xD;
             (relating to the completion of the course of antibiotics) within 4 weeks prior to&#xD;
             cycle 1 day 1&#xD;
&#xD;
          -  Patients with clinical suspicion of active or latent tuberculosis (to be confirmed by&#xD;
             a positive interferon gamma release assay)&#xD;
&#xD;
          -  Positive test results for chronic hepatitis B virus (HBV) infection (defined as&#xD;
             positive hepatitis B surface antigen [HBsAg] serology)&#xD;
&#xD;
             * Patients with occult or prior HBV infection (defined as negative HBsAg and positive&#xD;
             hepatitis B core antibody [HBcAb]) may be included if HBV deoxyribonucleic acid (DNA)&#xD;
             polymerase chain reaction (PCR) is undetectable, provided that they are willing to&#xD;
             undergo DNA testing on day 1 of every cycle and monthly for at least 12 months after&#xD;
             the last cycle of study treatment. Patients who have protective titers of hepatitis B&#xD;
             surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible&#xD;
&#xD;
          -  Positive test results for hepatitis C virus (HCV) antibody&#xD;
&#xD;
             * Patients who are positive for HCV antibody are eligible only if PCR is negative for&#xD;
             HCV ribonucleic acid (RNA)&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) seropositive status&#xD;
&#xD;
             * For patients with unknown HIV status, HIV testing will be performed at screening&#xD;
&#xD;
          -  Vaccination with a live vaccine within 28 days prior to treatment&#xD;
&#xD;
          -  Recent major surgery (within 6 weeks before the start of cycle 1 day 1) other than for&#xD;
             diagnosis&#xD;
&#xD;
          -  Women who are pregnant or lactating or who intend to become pregnant within a year of&#xD;
             the last dose of study treatment&#xD;
&#xD;
          -  Patients with a history of progressive multifocal leukoencephalopathy&#xD;
&#xD;
          -  Creatinine &gt; 1.5 x ULN or a measured creatinine clearance &lt; 40 mL/min (unless abnormal&#xD;
             laboratory values are due to underlying lymphoma per the investigator)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) &gt; 2.5 x ULN (unless&#xD;
             abnormal laboratory values are due to underlying lymphoma per the investigator)&#xD;
&#xD;
          -  Total bilirubin &gt;= 1.5 x ULN (unless abnormal laboratory values are due to underlying&#xD;
             lymphoma per the investigator)&#xD;
&#xD;
             * Patients with documented Gilbert disease may be enrolled if total bilirubin is =&lt; 3&#xD;
             x ULN&#xD;
&#xD;
          -  International normalized ratio (INR) or prothrombin time (PT) &gt; 1.5 x ULN in the&#xD;
             absence of therapeutic anticoagulation (unless abnormal laboratory values are due to&#xD;
             underlying lymphoma per the investigator)&#xD;
&#xD;
          -  Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) &gt;&#xD;
             1.5 x ULN in the absence of a lupus anticoagulant (unless abnormal laboratory values&#xD;
             are due to underlying lymphoma per the investigator)&#xD;
&#xD;
          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical&#xD;
             laboratory finding giving reasonable suspicion of a disease or condition that&#xD;
             contraindicates the use of an investigational drug or that may affect the&#xD;
             interpretation of the results or render the patient at high risk from treatment&#xD;
             complications&#xD;
&#xD;
          -  The use of Evushield or other post-exposure anti-viral medications against COVID19&#xD;
             does not affect study eligibility&#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>Dipenkumar Modi, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Barbara Ann Karmanos Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dipenkumar Modi, M.D.</last_name>
    <phone>(313) 576-8746</phone>
    <email>modid@karmanos.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Barbara Ann Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Clinical Trials Office</last_name>
      <phone>800-527-6266</phone>
    </contact>
    <investigator>
      <last_name>Asif Alavi, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Abhinav Deol, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Andrew Kin, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Dipenkumar Modi, M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Melissa Runge-Morris, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jay Yang, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Jeffrey Zonder, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Ali Gabali, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Suresh Balasubramanian, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Aasiya Matin, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Vijendra Singh, M.D.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>July 16, 2020</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 21, 2020</study_first_posted>
  <last_update_submitted>December 14, 2022</last_update_submitted>
  <last_update_submitted_qc>December 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Barbara Ann Karmanos Cancer Institute</investigator_affiliation>
    <investigator_full_name>Dipenkumar Modi</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Methylprednisolone Acetate</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Prednisolone acetate</mesh_term>
    <mesh_term>Hydrocortisone</mesh_term>
    <mesh_term>Cortisone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Liposomal doxorubicin</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
    <mesh_term>Prednisolone hemisuccinate</mesh_term>
    <mesh_term>Prednisolone phosphate</mesh_term>
    <mesh_term>Immunoconjugates</mesh_term>
    <mesh_term>Polatuzumab vedotin</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/NCT04479267
org study id: 2019-135
secondary id: P30CA022453
nct id: NCT04479267
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase II trial studies how well polatuzumab vedotin and combination chemotherapy work in
      treating patients with previously untreated double, triple hit lymphoma, Double Expressor
      Lymphoma or High-Grade B Cell Lymphoma. Polatuzumab vedotin is a monoclonal antibody that
      works by binding with cancer cells and releasing another chemotherapy drug, called monomethyl
      auristatin E, into the cell causing the cancer cells to die or stop growing. Chemotherapy
      drugs, such as rituximab, cyclophosphamide, doxorubicin, and prednisone, work in different
      ways to stop the growth of cancer cells, either by killing the cells, by stopping them from
      dividing, or by stopping them from spreading. Giving polatuzumab vedotin with combination
      chemotherapy may work better in treating patients with double or triple hit lymphoma compared
      to combination chemotherapy alone.
PRIMARY OBJECTIVE:

      I. To determine the rate of complete remission (CR) with polatuzumab vedotin plus rituximab,
      cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) in patients with newly
      diagnosed previously untreated double, triple hit lymphoma, Double Expressor Lymphoma or
      High-Grade B Cell Lymphoma. as measured by positron emission tomography (PET)-defined CR rate
      using the modified Lugano response criteria at the time of primary response assessment (6-8
      weeks after cycle 6 day 1 or last dose of study medication).

      PRIMARY OBJECTIVE:

      I. To determine the rate of complete remission (CR) with polatuzumab vedotin plus rituximab,
      cyclophosphamide, doxorubicin hydrochloride, and prednisone (R-CHP) in patients with newly
      diagnosed previously untreated double, triple hit lymphoma, Double Expressor Lymphoma or
      High-Grade B Cell Lymphoma. as measured by positron emission tomography (PET)-defined CR rate
      using the modified Lugano response criteria at the time of primary response assessment (6-8
      weeks after cycle 6 day 1 or last dose of study medication).

      SECONDARY SAFETY OBJECTIVE:

      I. To evaluate the safety and tolerability of the combination of polatuzumab vedotin (PoV)
      plus R-CHP as defined by Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

      SECONDARY EFFICACY OBJECTIVES:

      I. To assess the progression free survival (PFS) with PoV plus R-CHP in the above-mentioned
      patient population.

      II. To assess the overall survival (OS) with PoV plus R-CHP in the above-mentioned patient
      population.

      III. To assess the overall response rate (ORR; complete response [CR] or partial response
      [PR]) at the time of primary response assessment, based on modified Lugano PET-computed
      tomography (CT) criteria, as determined by the investigator.

      IV. To assess the duration of response (DOR) to PoV plus R-CHP based on PET-CT, as determined
      by the investigators in the above-mentioned patient population.

      EXPLORATORY OBJECTIVES:

      I. To explore the relationship between CD79b expression and response to treatment with PoV
      plus R-CHP.

      II. To explore the relationship between MYC expression and response to treatment with PoV
      plus R-CHP.

      III. To explore polatuzumab vedotin treatment on Myc protein expression.

      OUTLINE:

      Patients receive prednisone orally (PO), prednisolone intravenously (IV), or
      methylprednisolone IV on days 1-5. Patients also receive rituximab IV, polatuzumab vedotin IV
      over 30-90 minutes, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1. Treatment
      repeats every 21 days for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 12 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of complete remission
time frame: Up to 6-8 weeks after cycle 6 day 1 (cycles = 21 days) or last dose of study medication
description: Will be assessed by modified Lugano response criteria for malignant lymphoma. The complete remission rate will be summarized by a binomial response rate and its associated 2-sided 80% confidence interval (CI) using Pearson-Klopper method. The primary efficacy analysis will be also performed based on all response evaluable subjects as a sensitivity analysis.
measure: Incidence of adverse events
time frame: Up to 30 days after last dose of study treatment
description: Safety will be assessed through summaries of adverse events, summaries of changes from screening assessments in laboratory test results, electrocardiograms, and changes in vital signs. All adverse events occurring on or after first study treatment will be summarized by mapped term, appropriate thesaurus levels, and National Cancer Institute (NCI) Common Terminology Criteria Adverse Events version (v) 4.03 toxicity grade. All serious adverse events will be listed separately and summarized. Deaths reported during the study treatment period and those reported during follow-up after treatment discontinuation will be listed. Relevant laboratory and vital sign (temperature, heart rate, respiratory rate, pulse oximetry, and blood pressure) data will be displayed by time, with NCI Common Terminology Criteria for Adverse Events v5.0. Grade 3 and 4 values identified where appropriate.
measure: Progression-free survival (PFS)
time frame: From the start date of the treatment until the date of progression or death from any cause, whichever occurs first, assessed up to 12 months
description: The distribution of PFS will be graphically summarized using the Kaplan-Meier (KM) curve and the median PFS and its associated 2-sided CI will be estimated using the KM estimator. The median follow-up time and its 2-sided CI will be estimated using the reverse KM estimator.
measure: Overall response rate (ORR)
time frame: Up to 12 months
description: Will be defined as complete response (CR) or partial response (PR) at primary response assessment based on positron emission tomography/computed tomography as determined by the investigator and assessed using modified Lugano response criteria. CR and PR will be summarized using frequency and percentage. The ORR will be summarized by a binomial response rate and its associated 2-sided CI using Pearson-Klopper method.
measure: Duration of response (DOR)
time frame: From the date of CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is documented among all treated subjects who had a confirmed CR or PR, assessed up to 12 months
description: The distribution of DOR will be graphically summarized using the KM curve and the median PFS and its associated 2-sided CI will be estimated using the KM estimator.
measure: Biomarker assessment
time frame: Up to time of disease progression, assessed up to 12 months
description: Exploratory analyses of biomarkers related to tumor biology and the mechanisms of action of polatuzumab vedotin and rituximab will be conducted. Analyses will assess prognostic and/or predictive value of candidate biomarkers separately for each histological subtype and both investigator and Independent Review Committee assessed outcomes. Specifically, the association between candidate biomarkers and positron emission tomography (PET)-computed tomography (CT) CR rate and objective response rate and potentially other measures of efficacy and safety, independent of treatment, will be explored to assess potential prognostic value. In addition, the potential effect modification of treatment effect on PET-CT CR rate and OR rate and potentially other measures of efficacy and safety, by biomarker status, will be explored to assess potential predictive value.
arm group label: Treatment (polatuzumab vedotin, R-CHP)
arm group type: Experimental
description: Patients receive prednisone PO, prednisolone IV, or methylprednisolone IV on days 1-5. Patients also receive rituximab IV, polatuzumab vedotin IV over 30-90 minutes, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Prednisone
description: Given PO
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: .delta.1-Cortisone, 1, 2-Dehydrocortisone, 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione, 53-03-2, Adasone, Cortancyl, Dacortin, , Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome
intervention type: Drug
intervention name: Prednisolone
description: Given IV
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione, .delta.1-Hydrocortisone, 1,2-Dehydrohydrocortisone, 50-24-8, 9120, Adnisolone, Aprednislon, Capsoid, Cortalone, Cortisolone
intervention type: Drug
intervention name: Methylprednisolone
description: Given IV
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: (6alpha,11beta)-11,17,21-Trihydroxy-6-methylpregna-1,4-diene-3,20-dione, 6Alpha-Methylprednisolone, Adlone, Caberdelta M, DepMedalone, Depo Moderin, Depo-Nisolone, Duralone, Emmetipi, Esametone
intervention type: Biological
intervention name: Rituximab
description: Given IV
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: 174722-31-7, 687451, ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8
intervention type: Drug
intervention name: Polatuzumab Vedotin
description: Given IV
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: 1313206-42-6, ADC DCDS4501A, Antibody-Drug Conjugate DCDS4501A, DCDS4501A, FCU 2711, POLATUZUMAB VEDOTIN, polatuzumab vedotin-piiq, Polivy, RG7596, Ro 5541077-000
intervention type: Drug
intervention name: Cyclophosphamide
description: Given IV
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: 1-bis(2-chloroethyl)-amino-1-oxo-2-aza-5-oxaphosphoridin monohydrate, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate
intervention type: Drug
intervention name: Doxorubicin Hydrochloride
description: Given IV
arm group label: Treatment (polatuzumab vedotin, R-CHP)
other name: 14-Hydroxydaunorubicin Hydrochloride, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dipenkumar Modi, M.D.
role: Principal Investigator
affiliation: Barbara Ann Karmanos Institute
last name: Dipenkumar Modi, M.D.
phone: (313) 576-8746
email: modid@karmanos.org
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Barbara Ann Karmanos Cancer Institute
investigator full name: Dipenkumar Modi
investigator title: Principal Investigator
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Prednisone
mesh term: Methylprednisolone
mesh term: Methylprednisolone Acetate
mesh term: Methylprednisolone Hemisuccinate
mesh term: Prednisolone
mesh term: Prednisolone acetate
mesh term: Hydrocortisone
mesh term: Cortisone
mesh term: Cyclophosphamide
mesh term: Rituximab
mesh term: Doxorubicin
mesh term: Liposomal doxorubicin
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
mesh term: Prednisolone hemisuccinate
mesh term: Prednisolone phosphate
mesh term: Immunoconjugates
mesh term: Polatuzumab vedotin