<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/NCT04491955</url>
  </required_header>
  <id_info>
    <org_study_id>200138</org_study_id>
    <secondary_id>20-C-0138</secondary_id>
    <nct_id>NCT04491955</nct_id>
  </id_info>
  <brief_title>Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers</brief_title>
  <official_title>Phase II Trial of Combination Immunotherapy in Subjects With Advanced Small Bowel and Colorectal Cancers</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;
      Metastatic or refractory/recurrent small bowel and colorectal cancers cannot be cured and are&#xD;
      often not helped by standard treatments. Researchers want to find better treatments by&#xD;
      testing a combination of drugs.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To learn if a new combination of immunotherapy drugs can shrink tumors in people with&#xD;
      advanced small bowel and colorectal cancers.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People ages 18 and older who have advanced metastatic or refractory/recurrent small bowel&#xD;
      and/or colorectal cancer&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened on a separate protocol. They will have a physical exam and&#xD;
      medical history. They will have imaging scans. They will have blood and urine tests. Their&#xD;
      heart function will be measured. They may have a tumor biopsy.&#xD;
&#xD;
      Participants will repeat some of the screening tests during the study.&#xD;
&#xD;
      Participants will be put into study groups. Each group will get a combination of the&#xD;
      following drugs: CV301 vaccine (MVA-BN-CV301 and FPV-CV301), M7824, and N-803. Some will also&#xD;
      get NHS-IL12.&#xD;
&#xD;
      Participants will get the CV301 vaccines by injection under the skin. They will get M7824 by&#xD;
      intravenous infusion every 2 weeks. They will get N-803 by injection under the skin every 2&#xD;
      or 4 weeks. They may get NHS-IL12 by injection under the skin every 4 weeks. They will take&#xD;
      the study drugs for up to 1 year. They will visit the NIH every 2 weeks.&#xD;
&#xD;
      After treatment ends, participants will go to the clinic for a 28-day follow-up visit or have&#xD;
      a telephone call. They will be contacted every 3 months for 1 year, and then every 6 months&#xD;
      after that for the rest of their life.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
        -  Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and&#xD;
           poorly palliated by standard therapies. There is an unmet need for active treatments for&#xD;
           these tumors.&#xD;
&#xD;
        -  To date immunotherapies including anti PD-1 or anti PD-L1 inhibitors have proven largely&#xD;
           ineffective for the vast majority of these cancers.&#xD;
&#xD;
             -  In microsatellite stable (MSS) colorectal cancer (&gt;95% of these cancers) the&#xD;
                response rate to checkpoint inhibitors has been &lt;5%.&#xD;
&#xD;
             -  Preclinical studies suggest that the use of different combinations of multiple&#xD;
                immunotherapy agents may improve anti-tumor efficacy. These studies have employed&#xD;
                (1) a vaccine targeting a tumor associated antigen, (2) an IL-15 superagonist&#xD;
                (N-803, also known as ALT-803), (3) an anti-PD-L1 MAb or a bifunctional fusion&#xD;
                protein targeting PD-L1 and TGF beta (M7824), and (4) a tumor targeted&#xD;
                immunocytokine (NHS-IL12).&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      To evaluate the objective response rate (ORR) according to Response Evaluation Criteria&#xD;
      (RECIST 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting CEA and&#xD;
      MUC1, (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, (3) M7824 and&#xD;
      (4) NHS-IL12 (M9241) in subjects with advanced checkpoint naive MSS small bowel and&#xD;
      colorectal cancers.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  Age &gt;= 18 years old&#xD;
&#xD;
        -  Subjects with cytologically or histologically confirmed locally advanced or metastatic&#xD;
           small bowel or colorectal adenocarcinomas.&#xD;
&#xD;
        -  Prior first line systemic therapy is required unless the patient declines standard&#xD;
           treatment after appropriate counseling has been provided.&#xD;
&#xD;
        -  Subjects must have measurable disease.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This is a phase II trial of combination immunotherapy, with a brief dose escalation&#xD;
           portion for Arm 2.&#xD;
&#xD;
        -  The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm.&#xD;
&#xD;
        -  Patients will be enrolled on the following arms in sequential order: (1) Arm 1: CV301 +&#xD;
           M7824 + N-803, (2) Arm 2A and Arm 2B: CV301 + M7824 + N-803 + NHS-IL12; N-803 dose level&#xD;
           will be evaluated in Arm 2A prior to further enrollment in Arm 2B.&#xD;
&#xD;
        -  The first six patients on arm 1 will be evaluable for dose limiting toxicities (DLTs)&#xD;
           and accrual will only continue to 9 patients on that arm if less than 2 out of the first&#xD;
           6 patients experience a DLT.&#xD;
&#xD;
        -  In Arm 2B, patients will receive 4 drug treatments (CV301 + M7824 + N-803 + NHSIL12),&#xD;
           but the dose level of N-803 will first be determined during a 3-level dose escalation&#xD;
           portion, Arm 2A. Following determination of the MTD or highest safe dose evaluated, the&#xD;
           6 patients at that dose level will be included among the initial 9 patients for the&#xD;
           first stage of that arm.&#xD;
&#xD;
        -  If two or more out of nine patients have objective responses on a given arm that arm&#xD;
           will be expanded to enroll 20 evaluable patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 22, 2020</start_date>
  <completion_date type="Actual">February 28, 2023</completion_date>
  <primary_completion_date type="Actual">October 25, 2022</primary_completion_date>
  <phase>Phase 2</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>ORR for Triple Therapy</measure>
    <time_frame>one year</time_frame>
    <description>To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) CEA/ MUC1 vaccines, (2) N803 and (3) M7824 in subjects with advanced small bowel and colorectal cancers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>ORR for Quadruple Therapy</measure>
    <time_frame>one year</time_frame>
    <description>To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) CEA/ MUC1 vaccines, (2) N803, (3) M7824 and (4) NHS-IL12 in subjects with advanced small bowel and colorectal cancers.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of Triple Therapy</measure>
    <time_frame>one year</time_frame>
    <description>To evaluate the safety of the combination of (1) CV301, (2) N-803 and (3) M7824 in subjects with advanced small bowel and colorectal cancers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety of Quadruple Therapy</measure>
    <time_frame>one year</time_frame>
    <description>To evaluate the safety of the combination of (1) CV301, (2) N-803, (3) M7824 and (4) NHS-IL12 in subjects with advanced small bowel and colorectal cancers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS</measure>
    <time_frame>study end</time_frame>
    <description>To assess progression-free survival time (PFS) according to RECIST 1.1 per treatment assignment (three or four drug combination).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>study end</time_frame>
    <description>To assess overall survival (OS) per treatment assignment (three or four drug combination).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>study end</time_frame>
    <description>To assess duration of response per treatment assignment (three or four drug combination).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalization Due to PD AEs</measure>
    <time_frame>study end</time_frame>
    <description>To assess ratio of participants that are hospitalized because of adverse events attributed to disease progression</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">23</enrollment>
  <condition>Small Bowel Cancers</condition>
  <condition>Colorectal Cancers</condition>
  <arm_group>
    <arm_group_label>1/Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2/Arm 2A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3/Arm 2B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CV301</intervention_name>
    <description>CV301 vaccine consists of MVA-BN-CV301 and FPV-CV301. MVA-BN-CV301 (4 x 10^8 infectious units/0.5 mL each) will be administered as four subcutaneous injections on D1 and D15. Starting on D29, FPV-CV301 (1 x 10^9 infectious units/ 0.5mL) will be administered as a single subcutaneous injection every 4 weeks on Arm 1 or every 6 weeks on Arm 2A and 2B for up to one year.</description>
    <arm_group_label>1/Arm 1</arm_group_label>
    <arm_group_label>2/Arm 2A</arm_group_label>
    <arm_group_label>3/Arm 2B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MSB0011359C</intervention_name>
    <description>Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a &quot;flat&quot; dose of 1,200 mg or 300 mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.</description>
    <arm_group_label>1/Arm 1</arm_group_label>
    <arm_group_label>2/Arm 2A</arm_group_label>
    <arm_group_label>3/Arm 2B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-803</intervention_name>
    <description>N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every four weeks on Arm 1. N-803 will be administered at as dose of 10 (Micro)g/kg by SC injection every 4 weeks on Arm 2A and Arm 2B.</description>
    <arm_group_label>1/Arm 1</arm_group_label>
    <arm_group_label>2/Arm 2A</arm_group_label>
    <arm_group_label>3/Arm 2B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NHS-IL12</intervention_name>
    <description>NHS-IL12 will be given via subcutaneous injection at a dose of 8 mcg/kg every 4 weeks or 16 mcg/kg for the first 4 injections and 8 mcg/kg thereafter on Arms 2A and 2B.</description>
    <arm_group_label>2/Arm 2A</arm_group_label>
    <arm_group_label>3/Arm 2B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -INCLUSION CRITERIA:&#xD;
&#xD;
          1. Subjects with cytologically or histologically confirmed locally advanced or metastatic&#xD;
             small bowel or colorectal adenocarcinoma&#xD;
&#xD;
          2. Subjects must have received two prior lines of systemic therapy unless the subject is&#xD;
             not eligible to receive standard therapy or declines standard treatment&#xD;
&#xD;
          3. Subjects must have measurable disease&#xD;
&#xD;
          4. ECOG performance status &lt;= 2&#xD;
&#xD;
          5. Adequate hematologic function at screening, as follows:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt;=1 x 10^9/L&#xD;
&#xD;
               -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
               -  Platelets &gt;= 75,000/microliter&#xD;
&#xD;
          6. Adequate renal and hepatic function at screening, as follows:&#xD;
&#xD;
             - Serum creatinine &lt;= 1.5 x upper limit of normal (ULN) OR&#xD;
&#xD;
             Measured or calculated creatinine clearance &gt;= 40 mL/min for participant with&#xD;
             creatinine levels &gt; 1.5 X institutional ULN (GFR can also be used in place of&#xD;
             creatinine or CrCl);&#xD;
&#xD;
               -  Bilirubin &lt;= 1.5 x ULN OR in subjects with Gilbert s syndrome, a total bilirubin&#xD;
                  &lt;= 3.0 x ULN&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt;= 2.5 x ULN,&#xD;
                  unless liver metastases are present, then values must be &lt;= 3 x ULN)&#xD;
&#xD;
          7. The effects of the immunotherapies on the developing human fetus are unknown; thus,&#xD;
             women of childbearing potential and men must agree to use highly effective&#xD;
             contraception (hormonal or barrier method of birth control; abstinence) prior to study&#xD;
             entry, for the duration of study treatment and up to two months after the last dose of&#xD;
             study drug. Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
             partner is participating in this study, she should inform her treating physician&#xD;
             immediately.&#xD;
&#xD;
          8. Participants serologically positive for HIV, Hep B, Hep C are eligible as long as the&#xD;
             viral loads are undetectable by quantitative PCR. HIV positive participants must have&#xD;
             CD4 count &gt;= 200 cells per cubic millimeter at enrollment, be on stable antiretroviral&#xD;
             therapy for at least 4 weeks and have no reported opportunistic infections or&#xD;
             Castleman s disease within 12 months prior to enrollment.&#xD;
&#xD;
          9. Ability of subject to understand and the willingness to sign a written informed&#xD;
             consent document.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Participants with prior investigational drug, chemotherapy, immunotherapy or any prior&#xD;
             radiotherapy (except for palliative bone directed therapy) within the past 28 days&#xD;
             prior to the first drug administration except if the investigator has assessed that&#xD;
             all residual treatment-related toxicities have resolved or are minimal and feel the&#xD;
             participant is otherwise suitable for enrollment. Additionally, current therapies&#xD;
             (e.g., maintenance capecitabine) may be continued where in the opinion of the&#xD;
             investigator stopping such therapies may increase the risk of disease progression.&#xD;
             Also, participants may continue adjuvant hormonal therapy in the setting of a&#xD;
             definitively treated cancer (e.g. breast).&#xD;
&#xD;
          2. Participants with microsatellite unstable or mismatch repair deficient disease.&#xD;
&#xD;
          3. Major surgery within 28 days prior to the first drug administration (minimally&#xD;
             invasive procedures such as diagnostic biopsies are permitted).&#xD;
&#xD;
          4. Known life-threatening side effects resulting from prior checkpoint inhibitor therapy&#xD;
             (e.g., colitis, pneumonitis, fulminant hepatitis which led to permanent&#xD;
             discontinuation of prior checkpoint therapy). Autoimmune toxicity which was not life&#xD;
             threatening (e.g., arthritis) or did not lead to discontinuation of prior checkpoint&#xD;
             therapy is allowed.&#xD;
&#xD;
          5. Known active brain or central nervous system metastasis (less than a month out from&#xD;
             definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (&lt;3&#xD;
             months) or clinically significant cerebrovascular accident (&lt;3 months). In order to be&#xD;
             eligible participants must have repeat CNS imaging at least a month after definitive&#xD;
             treatment showing stable CNS disease. Participants with evidence of intratumoral or&#xD;
             peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is&#xD;
             grade &lt;= 1 and has been shown to be stable on two consecutive imaging scans.&#xD;
&#xD;
          6. Pregnant women are excluded from this study because these drugs have not been tested&#xD;
             in pregnant women and there is potential for teratogenic or abortifacient effects.&#xD;
             Because there is an unknown but potential risk for adverse events in nursing infants&#xD;
             secondary to treatment of the mother with these immunotherapies, breastfeeding should&#xD;
             be discontinued if the mother is treated on this protocol.&#xD;
&#xD;
          7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory&#xD;
             agent with exception of:&#xD;
&#xD;
               -  Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid&#xD;
                  disease or other mild autoimmune disorders not requiring immunosuppressive&#xD;
                  treatment;&#xD;
&#xD;
               -  Subjects requiring hormone replacement with corticosteroids are eligible if the&#xD;
                  steroids are administered only for the purpose of hormonal replacement and at&#xD;
                  doses &lt;= 10 mg of prednisone or equivalent per day;&#xD;
&#xD;
               -  Administration of steroids for other conditions through a route known to result&#xD;
                  in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation)&#xD;
                  is acceptable;&#xD;
&#xD;
               -  Subjects on systemic intravenous or oral corticosteroid therapy with the&#xD;
                  exception of physiologic doses of corticosteroids (&lt;= the equivalent of&#xD;
                  prednisone 10 mg/day) or other immunosuppressive agents such as azathioprine or&#xD;
                  cyclosporin A are excluded on the basis of potential immune suppression. For&#xD;
                  these subjects these excluded treatments must be discontinued at least 1 weeks&#xD;
                  prior to enrollment for recent short course use (&lt;= 14 days) or discontinued at&#xD;
                  least 4 weeks prior to enrollment for long term use (&gt; 14 days). In addition, the&#xD;
                  use of corticosteroids as premedication for contrast-enhanced studies is allowed&#xD;
                  prior to enrollment and on study.&#xD;
&#xD;
          8. Subjects with a history of serious intercurrent chronic or acute illness, such as&#xD;
             cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3&#xD;
             months) clinically significant bleeding events or other illness considered by the&#xD;
             Investigator as high risk for investigational drug treatment.&#xD;
&#xD;
          9. Subjects unwilling to accept blood products as medically indicated.&#xD;
&#xD;
         10. History of second malignancy within 3 years of enrollment except for the following:&#xD;
             adequately treated localized skin cancer, cervical carcinoma in situ, superficial&#xD;
             bladder cancer, or other localized malignancy which has been adequately treated or&#xD;
             malignancy which does not require active systemic treatment (e.g., low risk CLL).&#xD;
&#xD;
         11. Subjects with a known severe hypersensitivity reaction to a monoclonal antibody (grade&#xD;
             &gt;= 3 NCI-CTCAE v5) will be evaluated by the allergy/immunology team prior to&#xD;
             enrollment.&#xD;
&#xD;
         12. Receipt of any organ transplantation requiring ongoing immunosuppression.&#xD;
&#xD;
         13. Receipt of prior lymphodepleting chemotherapy (e.g. cyclophosphamide or fludarabine at&#xD;
             standard lymphodepleting doses).&#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>Julius Y Strauss, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-C-0138.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>March 28, 2023</verification_date>
  <study_first_submitted>July 29, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>March 29, 2023</last_update_submitted>
  <last_update_submitted_qc>March 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CEA MUC1 Vaccine</keyword>
  <keyword>CV301</keyword>
  <keyword>M7824</keyword>
  <keyword>N-803</keyword>
  <keyword>NHS-IL12</keyword>
  <keyword>Bintrafusp alfa</keyword>
  <keyword>M9241</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_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 available during the study and indefinitely.@@@@@@Genomic data are 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 are 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/NCT04491955
org study id: 200138
secondary id: 20-C-0138
nct id: NCT04491955
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Metastatic or refractory/recurrent small bowel and colorectal cancers cannot be cured and are
      often not helped by standard treatments. Researchers want to find better treatments by
      testing a combination of drugs.

      Objective:

      To learn if a new combination of immunotherapy drugs can shrink tumors in people with
      advanced small bowel and colorectal cancers.

      Eligibility:

      People ages 18 and older who have advanced metastatic or refractory/recurrent small bowel
      and/or colorectal cancer

      Design:

      Participants will be screened on a separate protocol. They will have a physical exam and
      medical history. They will have imaging scans. They will have blood and urine tests. Their
      heart function will be measured. They may have a tumor biopsy.

      Participants will repeat some of the screening tests during the study.

      Participants will be put into study groups. Each group will get a combination of the
      following drugs: CV301 vaccine (MVA-BN-CV301 and FPV-CV301), M7824, and N-803. Some will also
      get NHS-IL12.

      Participants will get the CV301 vaccines by injection under the skin. They will get M7824 by
      intravenous infusion every 2 weeks. They will get N-803 by injection under the skin every 2
      or 4 weeks. They may get NHS-IL12 by injection under the skin every 4 weeks. They will take
      the study drugs for up to 1 year. They will visit the NIH every 2 weeks.

      After treatment ends, participants will go to the clinic for a 28-day follow-up visit or have
      a telephone call. They will be contacted every 3 months for 1 year, and then every 6 months
      after that for the rest of their life.
Background:

        -  Metastatic or refractory/recurrent small bowel and colorectal cancers are incurable and
           poorly palliated by standard therapies. There is an unmet need for active treatments for
           these tumors.

        -  To date immunotherapies including anti PD-1 or anti PD-L1 inhibitors have proven largely
           ineffective for the vast majority of these cancers.

             -  In microsatellite stable (MSS) colorectal cancer (>95% of these cancers) the
                response rate to checkpoint inhibitors has been <5%.

             -  Preclinical studies suggest that the use of different combinations of multiple
                immunotherapy agents may improve anti-tumor efficacy. These studies have employed
                (1) a vaccine targeting a tumor associated antigen, (2) an IL-15 superagonist
                (N-803, also known as ALT-803), (3) an anti-PD-L1 MAb or a bifunctional fusion
                protein targeting PD-L1 and TGF beta (M7824), and (4) a tumor targeted
                immunocytokine (NHS-IL12).

      Objectives:

      To evaluate the objective response rate (ORR) according to Response Evaluation Criteria
      (RECIST 1.1) of the combination of (1) CV301, a poxviral based vaccine targeting CEA and
      MUC1, (2) N-803 and (3) M7824; and of the combination of (1) CV301, (2) N-803, (3) M7824 and
      (4) NHS-IL12 (M9241) in subjects with advanced checkpoint naive MSS small bowel and
      colorectal cancers.

      Eligibility:

        -  Age >= 18 years old

        -  Subjects with cytologically or histologically confirmed locally advanced or metastatic
           small bowel or colorectal adenocarcinomas.

        -  Prior first line systemic therapy is required unless the patient declines standard
           treatment after appropriate counseling has been provided.

        -  Subjects must have measurable disease.

      Design:

        -  This is a phase II trial of combination immunotherapy, with a brief dose escalation
           portion for Arm 2.

        -  The trial will be conducted using a Simon optimal two-stage design in each Phase II Arm.

        -  Patients will be enrolled on the following arms in sequential order: (1) Arm 1: CV301 +
           M7824 + N-803, (2) Arm 2A and Arm 2B: CV301 + M7824 + N-803 + NHS-IL12; N-803 dose level
           will be evaluated in Arm 2A prior to further enrollment in Arm 2B.

        -  The first six patients on arm 1 will be evaluable for dose limiting toxicities (DLTs)
           and accrual will only continue to 9 patients on that arm if less than 2 out of the first
           6 patients experience a DLT.

        -  In Arm 2B, patients will receive 4 drug treatments (CV301 + M7824 + N-803 + NHSIL12),
           but the dose level of N-803 will first be determined during a 3-level dose escalation
           portion, Arm 2A. Following determination of the MTD or highest safe dose evaluated, the
           6 patients at that dose level will be included among the initial 9 patients for the
           first stage of that arm.

        -  If two or more out of nine patients have objective responses on a given arm that arm
           will be expanded to enroll 20 evaluable patients.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: ORR for Triple Therapy
time frame: one year
description: To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) CEA/ MUC1 vaccines, (2) N803 and (3) M7824 in subjects with advanced small bowel and colorectal cancers.
measure: ORR for Quadruple Therapy
time frame: one year
description: To evaluate the objective response rate (ORR) according to Response Evaluation Criteria (RECIST 1.1) of the combination of (1) CEA/ MUC1 vaccines, (2) N803, (3) M7824 and (4) NHS-IL12 in subjects with advanced small bowel and colorectal cancers.
measure: Safety of Triple Therapy
time frame: one year
description: To evaluate the safety of the combination of (1) CV301, (2) N-803 and (3) M7824 in subjects with advanced small bowel and colorectal cancers.
measure: Safety of Quadruple Therapy
time frame: one year
description: To evaluate the safety of the combination of (1) CV301, (2) N-803, (3) M7824 and (4) NHS-IL12 in subjects with advanced small bowel and colorectal cancers.
measure: PFS
time frame: study end
description: To assess progression-free survival time (PFS) according to RECIST 1.1 per treatment assignment (three or four drug combination).
measure: Overall Survival
time frame: study end
description: To assess overall survival (OS) per treatment assignment (three or four drug combination).
measure: Duration of Response
time frame: study end
description: To assess duration of response per treatment assignment (three or four drug combination).
measure: Hospitalization Due to PD AEs
time frame: study end
description: To assess ratio of participants that are hospitalized because of adverse events attributed to disease progression
arm group label: 1/Arm 1
arm group type: Experimental
description: CEA/ MUC1 Vaccines + M7824 + N-803 (Triple Therapy).
arm group label: 2/Arm 2A
arm group type: Experimental
description: CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); dose escalation of NHS-IL12.
arm group label: 3/Arm 2B
arm group type: Experimental
description: CEA/ MUC1 Vaccines + M7824 + N-803 + NHSIL12 (Quadruple Therapy); fixed dose of NHS-IL12.
intervention type: Biological
intervention name: CV301
description: CV301 vaccine consists of MVA-BN-CV301 and FPV-CV301. MVA-BN-CV301 (4 x 10^8 infectious units/0.5 mL each) will be administered as four subcutaneous injections on D1 and D15. Starting on D29, FPV-CV301 (1 x 10^9 infectious units/ 0.5mL) will be administered as a single subcutaneous injection every 4 weeks on Arm 1 or every 6 weeks on Arm 2A and 2B for up to one year.
arm group label: 1/Arm 1
arm group label: 2/Arm 2A
arm group label: 3/Arm 2B
intervention type: Drug
intervention name: MSB0011359C
description: Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 50 to 80 minutes) once every 2 weeks. M7824 will be administered as a "flat" dose of 1,200 mg or 300 mg independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.
arm group label: 1/Arm 1
arm group label: 2/Arm 2A
arm group label: 3/Arm 2B
intervention type: Drug
intervention name: N-803
description: N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every four weeks on Arm 1. N-803 will be administered at as dose of 10 (Micro)g/kg by SC injection every 4 weeks on Arm 2A and Arm 2B.
arm group label: 1/Arm 1
arm group label: 2/Arm 2A
arm group label: 3/Arm 2B
intervention type: Drug
intervention name: NHS-IL12
description: NHS-IL12 will be given via subcutaneous injection at a dose of 8 mcg/kg every 4 weeks or 16 mcg/kg for the first 4 injections and 8 mcg/kg thereafter on Arms 2A and 2B.
arm group label: 2/Arm 2A
arm group label: 3/Arm 2B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Julius Y Strauss, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2020-C-0138.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
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 available during the study and indefinitely.@@@@@@Genomic data are 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 are made available via dbGaP through requests to the data custodians.