<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/NCT04432597</url>
  </required_header>
  <id_info>
    <org_study_id>200104</org_study_id>
    <secondary_id>20-C-0104</secondary_id>
    <nct_id>NCT04432597</nct_id>
  </id_info>
  <brief_title>HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PDL1/TGF-Beta Trap (M7824) in Subjects With HPV Associated Cancers</brief_title>
  <official_title>Phase I/II Trial of HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PD-L1/TGF-Beta Trap (M7824) in Subjects With HPV Positive 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;
      For some cancers associated with human papillomavirus (HPV), standard treatments are not&#xD;
      helpful. Researchers want to see if a vaccine for HPV combined with a drug called M7824 has a&#xD;
      better effect on these cancers than when they work alone.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To find a safe dose of HPV vaccine alone or combined with M7824. Also, to test if either HPV&#xD;
      vaccine alone or combined with M7824 causes a better immune response.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People ages 18 and older with locally advanced or metastatic HPV associated cancer (Phase I)&#xD;
      or stage II or III p16-positive oropharyngeal cancer (Phase II)&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Blood, urine, and heart tests&#xD;
&#xD;
      Possible photos of skin lesions&#xD;
&#xD;
      CT, MRI, or nuclear bone scan: Participants will lie in a machine that takes pictures of the&#xD;
      body. For the CT scan, they may have a contrast agent injected into a vein.&#xD;
&#xD;
      Participants may have up to 2 tumor biopsies. For participants in Phase II, this may be&#xD;
      performed with a thin tube placed through the nose into the airway.&#xD;
&#xD;
      Participants will receive the HPV vaccine alone or with M7824. For participants on the Phase&#xD;
      II, they will receive two doses of HPV vaccine under the skin either alone or with M7824 as&#xD;
      an infusion spaced two weeks apart. This will be done prior to their planned chemoradiation&#xD;
      or surgery. For participants on the Phase I, they will get the HPV vaccine injected under the&#xD;
      skin 2 to 3 times in the first month. Then they will have a booster every 4 weeks. They will&#xD;
      receive M7824 as an infusion into a vein every 2 weeks. Treatment will last up to 1 year.&#xD;
&#xD;
      After they stop treatment, participants will have a visit within 4 weeks. They will then be&#xD;
      contacted for long-term follow-up every year, for the rest of their lives.&#xD;
&#xD;
      ...&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
        -  Metastatic HPV associated malignancies (cervical, anal, oropharyngeal cancers, etc.) are&#xD;
           often incurable and poorly palliated by standard therapies.&#xD;
&#xD;
        -  HPV-positive (p16+) oropharyngeal cancers are the most common HPV-associated malignancy&#xD;
           in the United States and are increasing in incidence.&#xD;
&#xD;
        -  Stage II and III HPV-positive oropharyngeal cancer is primarily treated with definitive&#xD;
           therapy.&#xD;
&#xD;
        -  Although the prognosis for stage I HPV+ oropharyngeal cancer is favorable, about 20&#xD;
           percent of patients with stage II disease and 35 percent of patients with stage III&#xD;
           disease will die within four years.&#xD;
&#xD;
        -  Attempts to de-intensify treatment of HPV-positive oropharyngeal cancer by replacing&#xD;
           high-dose cisplatin with cetuximab concurrent with radiotherapy have failed.&#xD;
&#xD;
        -  Induction and neoadjuvant immunotherapy are an area of active study in this type of&#xD;
           cancer. The aims of induction immunotherapy are to induce antigen-specific immunity&#xD;
           prior to definitive therapy and to reduce the risk of disease relapse for patients with&#xD;
           stage II and III disease.&#xD;
&#xD;
        -  Therapeutic vaccines targeting HPV alone or in combination with M7824 (dual PD-L1 and&#xD;
           TGF beta inhibitor) have demonstrated induction of HPV antigen-specific responses and&#xD;
           tumor growth inhibition in multiple pre-clinical models of HPV-positive malignancy.&#xD;
&#xD;
        -  In clinical studies done in the CCR, M7824 as monotherapy has produced a notable&#xD;
           objective response rate (35-40%) for metastatic HPV + cancers including Oropharyngeal&#xD;
           Squamous Cell Carcinoma (OPSCC) and preclinical studies support the addition of an&#xD;
           investigational HPV vaccine with therapeutic intent (PRGN-2009, a gorilla adenoviral&#xD;
           based vaccine) to further increase anti-tumor efficacy.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Phase I in participants with recurrent/metastatic HPV positive cancer:&#xD;
&#xD;
      -Primary objective: To determine the safety and recommended phase II dose (RP2D) of PRGN-2009&#xD;
      (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg q2w.&#xD;
&#xD;
      Phase II in participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive&#xD;
      oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB/HPV +&#xD;
      sinonasal squamos cell cancer:&#xD;
&#xD;
      -Primary objective: To determine if HPV vaccine alone (Arm 2A) is able to result in a &gt;=&#xD;
      2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment&#xD;
      in p16-positive oropharyngeal cancer.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Phase I:&#xD;
&#xD;
        -  Men or women of age &gt;= 18 years old.&#xD;
&#xD;
        -  Subjects with cytologically or histologically confirmed locally advanced not amenable to&#xD;
           potentially curative local therapies or metastatic HPV associated malignancies:&#xD;
&#xD;
             -  Cervical cancers;&#xD;
&#xD;
             -  p16+ Oropharyngeal cancers;&#xD;
&#xD;
             -  Anal cancers;&#xD;
&#xD;
             -  Vulvar, vaginal, penile, and squamous cell rectal cancers&#xD;
&#xD;
             -  Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are&#xD;
                known HPV+.&#xD;
&#xD;
        -  Prior first line systemic therapy is required&#xD;
&#xD;
      Phase II:&#xD;
&#xD;
        -  Men or women of age &gt;= 18 years old.&#xD;
&#xD;
        -  Subjects with newly diagnosed stage I (T1,T2 N1), II or III II or III p16-positive&#xD;
           oropharyngeal squamous cell carcinoma (OPSCC) or stage II/III/IVA/IVB HPV-SNSCC planned&#xD;
           for definitive therapy.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Phase I: Recurrent/metastatic HPV associated cancer:&#xD;
&#xD;
        -  A 3+3 dose escalation design will be used which will evaluate PRGN-2009 (HPV vaccine) at&#xD;
           two dose levels (1x10^11 and 5x10^11 viral particle (VP) units) given as monotherapy&#xD;
           followed by a third dose level evaluating the RP2D dose of PRGN-2009 in combination with&#xD;
           1200 mg (RP2D) of M7824. In addition, the combination of PRGN-2009 at RP2D with 1200 mg&#xD;
           of M7824 will be expanded to a total of 10 evaluable participants to gauge the&#xD;
           preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with&#xD;
           advanced disease.&#xD;
&#xD;
        -  There will be a 4-week DLT evaluation period for each dose level.&#xD;
&#xD;
        -  It is expected that up to 22 participants may enroll.&#xD;
&#xD;
      Phase II:&#xD;
&#xD;
      Newly diagnosed p16-positive oropharyngeal cancer:&#xD;
&#xD;
        -  Evaluation of HPV vaccine alone (Arm 2A: Stage I (T1,T2 N1)/II/III) as neoadjuvant/&#xD;
           induction therapy before definitive standard of care therapy.&#xD;
&#xD;
        -  Participants will receive neoadjuvant/ induction immunotherapy at NIH Clinical Center&#xD;
           and then be referred back to their home institution for definitive standard of care&#xD;
           therapy.&#xD;
&#xD;
        -  It is expected that up to 20 participants may enroll.&#xD;
&#xD;
        -  Newly diagnosed stage II/III/IVA/IVB HPV-SNSCC:&#xD;
&#xD;
        -  Enrollment and treatment will occur similarly as participants with p16+oropharyngeal&#xD;
           cancer for exploratory correlates to advise possible future trials. Up to 2 participants&#xD;
           may enroll in this group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 11, 2020</start_date>
  <completion_date type="Anticipated">October 1, 2023</completion_date>
  <primary_completion_date type="Actual">November 22, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and recommended phase II dose of PRGN-2009</measure>
    <time_frame>one year</time_frame>
    <description>Phase I: In participants with recurrent/metastatic HPV positive cancer - To determine the safety and recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg q2w.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Level increase in CD3+ tumor infiltrating T cells post-treatment compared to pre-treatment</measure>
    <time_frame>one year</time_frame>
    <description>Phase II: In participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive oropharyngeal cancer - To determine if HPV vaccine alone (Arm 2A) is able to result in a equal to or greater than 2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment in p16-positive oropharyngeal cancer.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>ratio of participants that are hospitalized because of adverse events attributed to disease progression</measure>
    <time_frame>study end</time_frame>
    <description>Phase 1: To assess ratio of participants that are hospitalized because of adverse events attributed to disease progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-year overall and relapse-free survival rate for PRGN-2009 alone</measure>
    <time_frame>study end</time_frame>
    <description>Phase II: To determine the 3-year overall and relapse-free survival rate for PRGN-2009 alone (Arm 2A) as neoadjuvant/ induction therapy before definitive standard of care therapy for this population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OS)</measure>
    <time_frame>study end</time_frame>
    <description>Phase 1: To assess overall survival (OS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>progression-free survival time (PFS)</measure>
    <time_frame>study end</time_frame>
    <description>Phase 1: To assess progression-free survival time (PFS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>duration of response</measure>
    <time_frame>study end</time_frame>
    <description>Phase 1: To assess duration of response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone</measure>
    <time_frame>study end</time_frame>
    <description>Phase II: To assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone in this participant population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>does the use of PRGN-2009 alone result in significantly prolonged survival</measure>
    <time_frame>study end</time_frame>
    <description>Phase II: To determine if the use of PRGN-2009 alone results in significantly prolonged survival as compared to the expected 80% three-year historical survival for this population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall response rate (ORR)</measure>
    <time_frame>study end</time_frame>
    <description>Phase 1: To assess overall response rate (ORR) according to RECIST 1.1.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>HPV Positive Cancer</condition>
  <condition>Vulvar, Vaginal, Penile, Rectal Cancer</condition>
  <condition>Anal Cancer</condition>
  <condition>Oropharyngeal Cancer</condition>
  <condition>Cervical Cancer</condition>
  <arm_group>
    <arm_group_label>1/Arm 1A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HPV vaccine at 1x10(11) Viral Particles (VP) (DL1) and at 5x10(11) VP (DL2)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2/Arm 1B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HPV vaccine at RP2D plus M7824 at 1200 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3/Arm 2A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HPV vaccine at RP2D given as neoadjuvant or induction therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4/Arm 2B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HPV vaccine at RP2D plus M7824 at 1200 mg given as neoadjuvant or induction therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>PRGN-2009</intervention_name>
    <description>On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.</description>
    <arm_group_label>1/Arm 1A</arm_group_label>
    <arm_group_label>2/Arm 1B</arm_group_label>
    <arm_group_label>3/Arm 2A</arm_group_label>
    <arm_group_label>4/Arm 2B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>M7824</intervention_name>
    <description>Subjects enrolled to Arm 1B 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 independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.</description>
    <arm_group_label>2/Arm 1B</arm_group_label>
    <arm_group_label>4/Arm 2B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Subjects with cytologically or histologically confirmed locally advanced not amenable&#xD;
             to potentially curative local therapies or metastatic HPV associated malignancies&#xD;
             (Phase I only):&#xD;
&#xD;
               -  Cervical cancers;&#xD;
&#xD;
               -  p16+ Oropharyngeal cancers;&#xD;
&#xD;
               -  Anal cancers;&#xD;
&#xD;
               -  Vulvar, vaginal, penile, and squamous cell rectal cancers;&#xD;
&#xD;
               -  Other locally advanced or metastatic solid tumors (e.g., lung, esophagus) that&#xD;
                  are known HPV+.&#xD;
&#xD;
          -  Subjects with cytologically or histologically confirmed newly diagnosed stage II or&#xD;
             III p16-positive oropharyngeal squamous cell carcinoma planned for definitive therapy&#xD;
             or with newly diagnosed stage II or III or IVA or IVB HPV-positive sinonasal squamos&#xD;
             carcinoma (HPV-SNSCC) eligible for primary surgery (Phase II only).&#xD;
&#xD;
          -  Subjects must have measurable disease, per RECIST 1.1 (Phase 1 only).&#xD;
&#xD;
          -  Phase I only: Participants must have received one prior line of systemic chemotherapy&#xD;
             in the recurrent/metastatic setting as well as checkpoint blockade therapy in tumors&#xD;
             with FDA approval (head and neck squamous cell cancer and PDL1+ cervical cancer).&#xD;
             Exceptions to this include participants not eligible to receive standard therapy.&#xD;
&#xD;
          -  Men or Women; Age &gt;=18 years.&#xD;
&#xD;
          -  ECOG performance status =&lt; 2&#xD;
&#xD;
          -  Adequate hematologic function at screening, as follows:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt;=1 x 109/L;&#xD;
&#xD;
               -  Hemoglobin &gt;= 9 g/dL;&#xD;
&#xD;
               -  Platelets &gt;= 75,000/microliter.&#xD;
&#xD;
          -  Adequate renal and hepatic function at screening, as follows:&#xD;
&#xD;
               -  Serum creatinine =&lt; 1.5 x upper limit of normal (ULN) OR Measured or calculated&#xD;
                  creatinine clearance &gt;= 40 mL/min for participant with creatinine levels &gt; 1.5 X&#xD;
                  institutional ULN (GFR can also be used in place of 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;
          -  The effects of the immunotherapies (PRGN-2009 vaccine and M7824) on the developing&#xD;
             human fetus are unknown. For this reason and because M7824 and PRGN-2009 used in this&#xD;
             trial are possibly teratogenic, women of child-bearing potential and men must agree to&#xD;
             use highly effective contraception (hormonal or barrier method of birth control;&#xD;
             abstinence) prior to study entry and up to 2 months following the last dose of M7824&#xD;
             study treatment. Should a woman become pregnant or suspect she is pregnant while she&#xD;
             or her partner is participating in this study, she should inform her treating&#xD;
             physician immediately.&#xD;
&#xD;
          -  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;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Participants with prior investigational drug, live vaccine, chemotherapy,&#xD;
             immunotherapy or any prior radiotherapy (except for palliative bone directed therapy)&#xD;
             within the past 28 days prior to the first drug administration except if the&#xD;
             investigator has assessed that all residual treatment-related toxicities have resolved&#xD;
             or are minimal and feel the participant is otherwise suitable for enrollment.&#xD;
             Participants may continue adjuvant hormonal therapy in the setting of a definitively&#xD;
             treated cancer (e.g. breast).&#xD;
&#xD;
          -  Major surgery within 28 days prior to the first drug administration (minimally&#xD;
             invasive procedures such as diagnostic biopsies are permitted).&#xD;
&#xD;
          -  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 repeated 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;
          -  Pregnant women are excluded from this study because M7824 and PRGN-2009 vaccine have&#xD;
             not been tested in pregnant women and there is potential for teratogenic or&#xD;
             abortifacient effects. Because there is an unknown but potential risk for adverse&#xD;
             events in nursing infants secondary to treatment of the mother with these&#xD;
             immunotherapies, breastfeeding should be discontinued if the mother is treated on this&#xD;
             protocol.&#xD;
&#xD;
          -  Only for Phase I, Arm 1B: Active autoimmune disease that might deteriorate when&#xD;
             receiving an immunostimulatory 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;
               -  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&#xD;
&#xD;
        physiologic doses of corticosteroids (=&lt; the equivalent of prednisone 10 mg/day) or other&#xD;
        immunosuppressors such as azathioprine or cyclosporin A are excluded on the basis of&#xD;
        potential immune suppression. For these subjects these excluded treatments must be&#xD;
        discontinued at least 1 weeks prior to enrollment for recent short course use (=&lt; 14 days)&#xD;
        or discontinued at least 4 weeks prior to enrollment for long term use (&gt; 14 days). In&#xD;
        addition, the use of corticosteroids as premedication for contrast-enhanced studies is&#xD;
        allowed prior to enrollment and on study.&#xD;
&#xD;
          -  Only for Phase I: Subjects with a history of serious intercurrent chronic or acute&#xD;
             illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or&#xD;
             recent (within 3 months) clinically significant bleeding events, known left&#xD;
             ventricular ejection fraction &lt;50% (confirmation of EF &gt; 50% is not required for&#xD;
             eligibility), history of myocarditis, or recent myocardial infarction (within 6&#xD;
             months), or other illness considered by the Investigator as high risk for M7824 drug&#xD;
             treatment.&#xD;
&#xD;
          -  Only for Phase I: Subjects refusing to accept blood products as medically indicated.&#xD;
&#xD;
          -  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, other localized malignancy which has been adequately treated or&#xD;
             malignancy which does not require active systemic treatment (e.g., low risk CLL). For&#xD;
             participants enrolled on the phase I portion of the protocol a second HPV driven&#xD;
             malignancy is allowed.&#xD;
&#xD;
          -  Only for Phase I, Arm 1B: Subjects with a known severe hypersensitivity reaction to&#xD;
             monoclonal antibodies or its excipients (grade &gt;/= 3 NCI-CTCAE v5) will be evaluated&#xD;
             by the allergy/immunology team prior to enrollment.&#xD;
&#xD;
          -  Prior allogenic tissue/solid organ transplant.&#xD;
&#xD;
          -  For participants who may receive M7824: previous life-threatening side effects&#xD;
             resulting from prior checkpoint inhibitor therapy.&#xD;
&#xD;
          -  Participants with pulse oximetry &lt; 92% on room air at screening.&#xD;
&#xD;
          -  Participants unable to provide informed consent.&#xD;
&#xD;
          -  Participants whose inclusion in the trial would in the judgement of the PI lead to&#xD;
             time from diagnosis to initiation of curative treatment of&gt;70 days (Arm 2A only).&#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>Charalampos Floudas, 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-0104.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>April 21, 2023</verification_date>
  <study_first_submitted>June 13, 2020</study_first_submitted>
  <study_first_submitted_qc>June 13, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>April 22, 2023</last_update_submitted>
  <last_update_submitted_qc>April 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HPV Associated Malignancy</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>HPV Vaccine</keyword>
  <keyword>PRGN-2009</keyword>
  <keyword>M7824</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anus Neoplasms</mesh_term>
    <mesh_term>Oropharyngeal 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/NCT04432597
org study id: 200104
secondary id: 20-C-0104
nct id: NCT04432597
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      For some cancers associated with human papillomavirus (HPV), standard treatments are not
      helpful. Researchers want to see if a vaccine for HPV combined with a drug called M7824 has a
      better effect on these cancers than when they work alone.

      Objective:

      To find a safe dose of HPV vaccine alone or combined with M7824. Also, to test if either HPV
      vaccine alone or combined with M7824 causes a better immune response.

      Eligibility:

      People ages 18 and older with locally advanced or metastatic HPV associated cancer (Phase I)
      or stage II or III p16-positive oropharyngeal cancer (Phase II)

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Blood, urine, and heart tests

      Possible photos of skin lesions

      CT, MRI, or nuclear bone scan: Participants will lie in a machine that takes pictures of the
      body. For the CT scan, they may have a contrast agent injected into a vein.

      Participants may have up to 2 tumor biopsies. For participants in Phase II, this may be
      performed with a thin tube placed through the nose into the airway.

      Participants will receive the HPV vaccine alone or with M7824. For participants on the Phase
      II, they will receive two doses of HPV vaccine under the skin either alone or with M7824 as
      an infusion spaced two weeks apart. This will be done prior to their planned chemoradiation
      or surgery. For participants on the Phase I, they will get the HPV vaccine injected under the
      skin 2 to 3 times in the first month. Then they will have a booster every 4 weeks. They will
      receive M7824 as an infusion into a vein every 2 weeks. Treatment will last up to 1 year.

      After they stop treatment, participants will have a visit within 4 weeks. They will then be
      contacted for long-term follow-up every year, for the rest of their lives.

      ...
Background

        -  Metastatic HPV associated malignancies (cervical, anal, oropharyngeal cancers, etc.) are
           often incurable and poorly palliated by standard therapies.

        -  HPV-positive (p16+) oropharyngeal cancers are the most common HPV-associated malignancy
           in the United States and are increasing in incidence.

        -  Stage II and III HPV-positive oropharyngeal cancer is primarily treated with definitive
           therapy.

        -  Although the prognosis for stage I HPV+ oropharyngeal cancer is favorable, about 20
           percent of patients with stage II disease and 35 percent of patients with stage III
           disease will die within four years.

        -  Attempts to de-intensify treatment of HPV-positive oropharyngeal cancer by replacing
           high-dose cisplatin with cetuximab concurrent with radiotherapy have failed.

        -  Induction and neoadjuvant immunotherapy are an area of active study in this type of
           cancer. The aims of induction immunotherapy are to induce antigen-specific immunity
           prior to definitive therapy and to reduce the risk of disease relapse for patients with
           stage II and III disease.

        -  Therapeutic vaccines targeting HPV alone or in combination with M7824 (dual PD-L1 and
           TGF beta inhibitor) have demonstrated induction of HPV antigen-specific responses and
           tumor growth inhibition in multiple pre-clinical models of HPV-positive malignancy.

        -  In clinical studies done in the CCR, M7824 as monotherapy has produced a notable
           objective response rate (35-40%) for metastatic HPV + cancers including Oropharyngeal
           Squamous Cell Carcinoma (OPSCC) and preclinical studies support the addition of an
           investigational HPV vaccine with therapeutic intent (PRGN-2009, a gorilla adenoviral
           based vaccine) to further increase anti-tumor efficacy.

      Objectives:

      Phase I in participants with recurrent/metastatic HPV positive cancer:

      -Primary objective: To determine the safety and recommended phase II dose (RP2D) of PRGN-2009
      (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg q2w.

      Phase II in participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive
      oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB/HPV +
      sinonasal squamos cell cancer:

      -Primary objective: To determine if HPV vaccine alone (Arm 2A) is able to result in a >=
      2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment
      in p16-positive oropharyngeal cancer.

      Eligibility:

      Phase I:

        -  Men or women of age >= 18 years old.

        -  Subjects with cytologically or histologically confirmed locally advanced not amenable to
           potentially curative local therapies or metastatic HPV associated malignancies:

             -  Cervical cancers;

             -  p16+ Oropharyngeal cancers;

             -  Anal cancers;

             -  Vulvar, vaginal, penile, and squamous cell rectal cancers

             -  Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are
                known HPV+.

        -  Prior first line systemic therapy is required

      Phase II:

        -  Men or women of age >= 18 years old.

        -  Subjects with newly diagnosed stage I (T1,T2 N1), II or III II or III p16-positive
           oropharyngeal squamous cell carcinoma (OPSCC) or stage II/III/IVA/IVB HPV-SNSCC planned
           for definitive therapy.

      Design:

      Phase I: Recurrent/metastatic HPV associated cancer:

        -  A 3+3 dose escalation design will be used which will evaluate PRGN-2009 (HPV vaccine) at
           two dose levels (1x10^11 and 5x10^11 viral particle (VP) units) given as monotherapy
           followed by a third dose level evaluating the RP2D dose of PRGN-2009 in combination with
           1200 mg (RP2D) of M7824. In addition, the combination of PRGN-2009 at RP2D with 1200 mg
           of M7824 will be expanded to a total of 10 evaluable participants to gauge the
           preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with
           advanced disease.

        -  There will be a 4-week DLT evaluation period for each dose level.

        -  It is expected that up to 22 participants may enroll.

      Phase II:

      Newly diagnosed p16-positive oropharyngeal cancer:

        -  Evaluation of HPV vaccine alone (Arm 2A: Stage I (T1,T2 N1)/II/III) as neoadjuvant/
           induction therapy before definitive standard of care therapy.

        -  Participants will receive neoadjuvant/ induction immunotherapy at NIH Clinical Center
           and then be referred back to their home institution for definitive standard of care
           therapy.

        -  It is expected that up to 20 participants may enroll.

        -  Newly diagnosed stage II/III/IVA/IVB HPV-SNSCC:

        -  Enrollment and treatment will occur similarly as participants with p16+oropharyngeal
           cancer for exploratory correlates to advise possible future trials. Up to 2 participants
           may enroll in this group.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and recommended phase II dose of PRGN-2009
time frame: one year
description: Phase I: In participants with recurrent/metastatic HPV positive cancer - To determine the safety and recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg q2w.
measure: Level increase in CD3+ tumor infiltrating T cells post-treatment compared to pre-treatment
time frame: one year
description: Phase II: In participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive oropharyngeal cancer - To determine if HPV vaccine alone (Arm 2A) is able to result in a equal to or greater than 2-fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre-treatment in p16-positive oropharyngeal cancer.
measure: ratio of participants that are hospitalized because of adverse events attributed to disease progression
time frame: study end
description: Phase 1: To assess ratio of participants that are hospitalized because of adverse events attributed to disease progression.
measure: 3-year overall and relapse-free survival rate for PRGN-2009 alone
time frame: study end
description: Phase II: To determine the 3-year overall and relapse-free survival rate for PRGN-2009 alone (Arm 2A) as neoadjuvant/ induction therapy before definitive standard of care therapy for this population.
measure: overall survival (OS)
time frame: study end
description: Phase 1: To assess overall survival (OS).
measure: progression-free survival time (PFS)
time frame: study end
description: Phase 1: To assess progression-free survival time (PFS).
measure: duration of response
time frame: study end
description: Phase 1: To assess duration of response.
measure: assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone
time frame: study end
description: Phase II: To assess the safety of the recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone in this participant population.
measure: does the use of PRGN-2009 alone result in significantly prolonged survival
time frame: study end
description: Phase II: To determine if the use of PRGN-2009 alone results in significantly prolonged survival as compared to the expected 80% three-year historical survival for this population.
measure: overall response rate (ORR)
time frame: study end
description: Phase 1: To assess overall response rate (ORR) according to RECIST 1.1.
arm group label: 1/Arm 1A
arm group type: Experimental
description: HPV vaccine at 1x10(11) Viral Particles (VP) (DL1) and at 5x10(11) VP (DL2)
arm group label: 2/Arm 1B
arm group type: Experimental
description: HPV vaccine at RP2D plus M7824 at 1200 mg
arm group label: 3/Arm 2A
arm group type: Experimental
description: HPV vaccine at RP2D given as neoadjuvant or induction therapy
arm group label: 4/Arm 2B
arm group type: Experimental
description: HPV vaccine at RP2D plus M7824 at 1200 mg given as neoadjuvant or induction therapy
intervention type: Biological
intervention name: PRGN-2009
description: On the phase I portion of the protocol PRGN-2009 will be administered on D1, D15, D29 followed by booster vaccines every 4 weeks for up to a year. The dose level given as booster will be the same dose participants will be receiving for D1, D15 and D29. On the phase II portion of the protocol PRGN-2009 will be administered on just D1 and D15.
arm group label: 1/Arm 1A
arm group label: 2/Arm 1B
arm group label: 3/Arm 2A
arm group label: 4/Arm 2B
intervention type: Biological
intervention name: M7824
description: Subjects enrolled to Arm 1B 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 independent of body weight. M7824 is administered as an intravenous infusion with a mandatory 0.2 micron in-line filter.
arm group label: 2/Arm 1B
arm group label: 4/Arm 2B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Charalampos Floudas, 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-0104.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Anus Neoplasms
mesh term: Oropharyngeal 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.