<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/NCT03003468</url>
  </required_header>
  <id_info>
    <org_study_id>BTCRC-LUN15-017</org_study_id>
    <nct_id>NCT03003468</nct_id>
  </id_info>
  <brief_title>Pembrolizumab + Imprime PGG for Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy: Big Ten Cancer Research Consortium BTCRC-LUN15-017</brief_title>
  <official_title>A Phase Ib/II Study of Anti-PD-1 Antibody Pembrolizumab and Imprime PGG for Patients With Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy: Big Ten Cancer Research Consortium BTCRC-LUN15-017</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawrence Feldman, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>HiberCell, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Big Ten Cancer Research Consortium</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label, multi-institutional, single arm study with a dose escalation phase Ib&#xD;
      cohort, followed by a phase II cohort of pembrolizumab and Imprime PGG. No randomization or&#xD;
      blinding is involved.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OUTLINE: This is a multi-center study.&#xD;
&#xD;
      The phase Ib dose escalation will evaluate the combination of pembrolizumab and Imprime PGG&#xD;
      for subjects with metastatic non-small cell lung cancer (NSCLC) after progression on&#xD;
      first-line platinum-based chemotherapy. The phase II trial will test whether addition of&#xD;
      Imprime PGG to pembrolizumab will increase median progression-free survival (PFS) in second&#xD;
      line therapy setting in NSCLC.&#xD;
&#xD;
      PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:&#xD;
&#xD;
      Cohort 1 will consist of 3-6 patients who will receive&#xD;
&#xD;
        -  Imprime PGG 2 mg/kg IV on Days 1, 8, 15 for Cycles 1-4&#xD;
&#xD;
        -  Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16&#xD;
&#xD;
        -  Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)&#xD;
&#xD;
      Cohort 2 will consist of 3-6 patients who will receive&#xD;
&#xD;
        -  Imprime PGG 4 mg/kg IV on Days 1, 8, 15 for Cycles 1-4&#xD;
&#xD;
        -  Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16&#xD;
&#xD;
        -  Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)&#xD;
&#xD;
      If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of&#xD;
      therapy, an additional three subjects will be enrolled at dose level 2. If all subjects in&#xD;
      dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be&#xD;
      enrolled into dose level 2 to ensure only 0-1 of 6 subjects have a DLT. There will be no&#xD;
      further escalation beyond dose level 2.&#xD;
&#xD;
      PHASE II INVESTIGATIONAL TREATMENT:&#xD;
&#xD;
      Pembrolizumab will be given on Day 1 of each 21 day cycle after Imprime PGG, and the RP2D&#xD;
      dose of Imprime PGG will be given on Days 1, 8 and 15 of each 21 day cycle. Treatment will&#xD;
      continue up to 16 cycles, or until disease progression, unacceptable toxicity, subject&#xD;
      refusal, or subject death either from progression of disease, the therapy itself, or from&#xD;
      other causes.&#xD;
&#xD;
      Life expectancy: of 6 months or greater&#xD;
&#xD;
      The following baseline labs must be completed within 28 days prior to registration for&#xD;
      protocol therapy:&#xD;
&#xD;
      Hepatic:&#xD;
&#xD;
        -  total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for&#xD;
           subjects with total bilirubin levels &gt; 1.5 x ULN (except subject with Gilbert's&#xD;
           Syndrome, who can have total bilirubin &lt; 3.0 mg/dl)&#xD;
&#xD;
        -  aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known&#xD;
           hepatic metastases&#xD;
&#xD;
        -  alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic&#xD;
           metastases&#xD;
&#xD;
      Renal:&#xD;
&#xD;
        -  Serum creatinine ≤ 3 mg/dL OR&#xD;
&#xD;
        -  if serum creatinine &gt; 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min&#xD;
&#xD;
      Hematopoietic:&#xD;
&#xD;
        -  hemoglobin ≥ 9 g/dL, subjects requiring transfusion will not be eligible to start study&#xD;
&#xD;
        -  and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L&#xD;
&#xD;
        -  and platelet count ≥ 100 × 10^9/L&#xD;
&#xD;
      Coagulation:&#xD;
&#xD;
        -  INR &lt; 1.5 × ULN OR&#xD;
&#xD;
        -  for subjects receiving anticoagulant, the subjects must, in the investigator's opinion,&#xD;
           be clinically stable with no evidence of active bleeding while receiving anticoagulant&#xD;
           therapy. The INR for subjects on warfarin should be in the therapeutic range. Low&#xD;
           molecular weight heparin (LMWH) is allowed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 13, 2017</start_date>
  <completion_date type="Anticipated">October 2025</completion_date>
  <primary_completion_date type="Actual">June 6, 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>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Open Label</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Phase Ib: Maximum Tolerated Dose</measure>
    <time_frame>From the start of combination treatment until completion of the first cycle of treatment (21 days)</time_frame>
    <description>Phase Ib: Maximum tolerated dose (MTD) for subjects receiving Imprime PGG with pembrolizumab without experiencing dose-limiting toxicity(s) (DLT) per Common Terminology Criteria for Adverse Events (CTCAE) v4.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Progression Free Survival</measure>
    <time_frame>From the date of enrollment until the criteria for disease progression is met as defined by RECIST 1.1 or death from any cause, whichever occurs first (up to 1 year from start of treatment)</time_frame>
    <description>Progression-free survival (PFS) with Imprime PGG and pembrolizumab combination therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assess Adverse Effects</measure>
    <time_frame>From start of treatment D1 and every treatment visit thereafter (up to 11 months [16 cycles])</time_frame>
    <description>Number of Participants with Adverse Events as a Measure of Safety and Tolerability per Common Terminology Criteria for Adverse Events (CTCAE) v4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Ratio</measure>
    <time_frame>From the start of treatment D1 assessed every 6 weeks +/- 1 week while on study treatment (up to 11 months [16 cycles])</time_frame>
    <description>Clinical Benefit Ratio (complete, partial response, or stable disease) as assessed per RECIST 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) at 6 months</measure>
    <time_frame>6 months</time_frame>
    <description>Estimate Progression-Free Survival (PFS) and 6-month PFS using RECIST v1.1 in subjects with NSCLC when treated with Imprime PGG in combination with pembrolizumab who progressed after first-line systemic therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>from the start of the treatment until death from any cause (up to 1 year from start of treatment)</time_frame>
    <description>To determine the overall survival for this patient population at 1 year.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Non-Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Arm A - Phase Ib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose Escalation Cohort Cohort 1 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 of each 21 day cycle. Imprime PGG will be administered at 2mg/kg on Day 1,8, and 15 of cycles 1-4, and on Day 1 of cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.&#xD;
Experimental: Arm A - Phase II Investigational Treatment The maximum safe dose of Imprime PGG in combination with pembrolizumab (as determined in the phase Ib cohort) will be given on Day 1,8, and 15 for cycles 1-4, and on Day 1 of cycles 5-16.&#xD;
Cohort 2 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 and Imprime PGG at 4mg/kg on Day 1,8, and 15 for Cycles 1-4 and on Day 1 only for Cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imprime PGG</intervention_name>
    <description>Arm A: Phase Ib Cohort 1: 2mg/kg IV; Arm A: Phase Ib Cohort 2: 4mg/kg IV</description>
    <arm_group_label>Arm A - Phase Ib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MK-3475</intervention_name>
    <description>200mg IV</description>
    <arm_group_label>Arm A - Phase Ib</arm_group_label>
    <other_name>pembrolizumab</other_name>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imprime PGG</intervention_name>
    <description>Arm B: Phase II treatment: administered at the maximum safe dose of 2mg or 4 mg as established in the Phase Ib cohort study.</description>
    <arm_group_label>Arm A - Phase Ib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female ≥ 18 years of age at time of consent.&#xD;
&#xD;
          -  Subjects with histologically or cytologically confirmed non-small cell lung cancer&#xD;
             (NCSLC).&#xD;
&#xD;
          -  Subjects with stage IV non-small cell lung cancer as defined by American Joint&#xD;
             Committee on Cancer (AJCC).&#xD;
&#xD;
          -  Phase Ib: Subjects who progressed after first-line platinum-based chemotherapy and who&#xD;
             are candidates for second-line therapy.&#xD;
&#xD;
          -  Phase II: Subjects who have progressed on first-line systemic therapy (either&#xD;
             platinum-based chemotherapy with or without immune checkpoint inhibitor or immune&#xD;
             checkpoint inhibitor as first line therapy) who are candidates for second-line&#xD;
             systemic therapy. Patients with early stage cancer will also be eligible if&#xD;
             progression occurs:&#xD;
&#xD;
               -  within 6 months of adjuvant chemotherapy after curative resection&#xD;
&#xD;
               -  within 6 months of adjuvant chemotherapy after curative resection while on&#xD;
                  adjuvant immunotherapy, currently only available as part of a clinical trial&#xD;
&#xD;
               -  within 6 months of curative surgery if chemotherapy is given in the neoadjuvant&#xD;
                  setting&#xD;
&#xD;
               -  within 6 months of completion of chemoradiation (or 6 months from completion of&#xD;
                  consolidation chemotherapy if administered after concurrent chemoradiation)&#xD;
&#xD;
               -  within 6 months of completion of chemoradiation or consolidation chemotherapy (if&#xD;
                  administered) while on consolidation immunotherapy, a setting for which&#xD;
                  durvalumab is FDA approved.&#xD;
&#xD;
          -  Phase II: Subjects with an EGFR or ALK mutation who are no longer candidates for TKI&#xD;
             therapy and have progressed on standard systemic therapy (either platinum-based&#xD;
             chemotherapy with or without immune checkpoint inhibitor or immune checkpoint&#xD;
             inhibitor as first line therapy).&#xD;
&#xD;
          -  Phase II only: Measurable disease according to RECIST v1.1 (Section 8) obtained by&#xD;
             imaging within 28 days prior to study registration. Phase Ib: subjects may enroll with&#xD;
             or without measurable disease.&#xD;
&#xD;
          -  Phase II only: Subjects must have presence of peripheral blood levels of IgG&#xD;
             anti-β-glucan antibody (ABA) of ≥ 20 μg/mL as determined by an ELISA test within 90&#xD;
             days prior to study registration.&#xD;
&#xD;
          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2&#xD;
             within 28 days prior to study registration.&#xD;
&#xD;
          -  Life expectancy of 6 months or greater as determined by the treating physician.&#xD;
&#xD;
          -  Adequate hepatic function within 28 days prior to study registration defined as&#xD;
             meeting all of the following criteria:&#xD;
&#xD;
               -  total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for&#xD;
                  subjects with total bilirubin levels &gt; 1.5 x ULN (except subject with Gilbert's&#xD;
                  Syndrome, who can have total bilirubin &lt; 3.0 mg/dl)&#xD;
&#xD;
               -  aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known&#xD;
                  hepatic metastases&#xD;
&#xD;
               -  alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known&#xD;
                  hepatic metastases&#xD;
&#xD;
          -  Adequate renal function within 28 days prior to study registration defined by either&#xD;
             of the following criteria:&#xD;
&#xD;
               -  Serum creatinine ≤ 3 mg/dL&#xD;
&#xD;
               -  if serum creatinine &gt; 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20&#xD;
                  mL/min&#xD;
&#xD;
          -  Adequate hematologic function within 28 days prior to study registration defined as&#xD;
             meeting all of the following criteria:&#xD;
&#xD;
               -  hemoglobin ≥ 9 g/dL; subjects requiring transfusion will be eligible to start&#xD;
                  study&#xD;
&#xD;
               -  and absolute neutrophil count (ANC) ≥ 1.5 × 109/L&#xD;
&#xD;
               -  and platelet count ≥ 100 × 109/L&#xD;
&#xD;
          -  Adequate coagulation functioning within 28 days prior to study registration defined by&#xD;
             either of the following criteria:&#xD;
&#xD;
               -  INR &lt; 1.5 × ULN&#xD;
&#xD;
               -  for subjects receiving anticoagulant, the subjects must, in the investigator's&#xD;
                  opinion, be clinically stable with no evidence of active bleeding while receiving&#xD;
                  anticoagulant therapy. The INR for subjects on warfarin should be in the&#xD;
                  therapeutic range. Low molecular weight heparin (LMWH) is allowed.&#xD;
&#xD;
          -  Provided written informed consent and HIPAA authorization for release of personal&#xD;
             health information, approved by an Institutional Review Board (IRB). NOTE: HIPAA&#xD;
             authorization may be included in the informed consent or obtained separately.&#xD;
&#xD;
          -  Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A&#xD;
             negative serum or urine pregnancy test is required within 72 hours of study&#xD;
             registration. If the urine test cannot be confirmed as negative, a serum pregnancy&#xD;
             test will be required.&#xD;
&#xD;
          -  Women of childbearing potential (WOCP) must be willing to use two effective methods of&#xD;
             birth control such as an oral, implantable, injectable, or transdermal hormonal&#xD;
             contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms,&#xD;
             sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total&#xD;
             abstinence for the course of the study until 120 days after the last dose of study&#xD;
             drug. NOTE: Women are considered to be of childbearing potential unless they are&#xD;
             postmenopausal (≥45 years of age and has not had menses for greater than 12&#xD;
             consecutive months), surgically sterile (bilateral tubal ligation, bilateral&#xD;
             oophorectomy, or hysterectomy) or not heterosexually active for the duration of the&#xD;
             study and at least 120 days after the last dose of study drug.&#xD;
&#xD;
          -  Men who are not surgically sterile (vasectomy) must agree to use an acceptable method&#xD;
             of contraception. Male subjects with female sexual partners who are pregnant, possibly&#xD;
             pregnant, or who could become pregnant during the study must agree to use condoms from&#xD;
             the first dose of study drug through at least 120 days after the last dose of study&#xD;
             drug. Total abstinence for the same study period is an acceptable alternative.&#xD;
&#xD;
          -  Willingness and ability to comply with scheduled visits (including geographical&#xD;
             distance), treatment plans, laboratory tests, and other study procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Surgery within 4 weeks prior to study registration except for minor procedures. NOTE:&#xD;
             Hepatic biliary stent placement, PleurX catheter, port replacement, ureteral stent or&#xD;
             other minor surgeries are allowed. NOTE: Subject must have adequately recovered from&#xD;
             the toxicity and/or complications of major surgery prior to study registration, as&#xD;
             determined by the treating physician.&#xD;
&#xD;
          -  Patients with known untreated or active central nervous system (CNS) metastases.&#xD;
             Subjects suspected to have brain mets should undergo brain MRI (or CT head if MRI is&#xD;
             not feasible) to exclude brain metastases. Patients with treated brain metastases will&#xD;
             be eligible as long as their symptoms are improving or achieved new baseline and not&#xD;
             requiring steroids for at least 2 weeks. Patients with leptomeningeal disease will be&#xD;
             excluded regardless of clinical stability.&#xD;
&#xD;
          -  Previously received a solid organ transplant or allogeneic progenitor/stem cell&#xD;
             transplant.&#xD;
&#xD;
          -  Received a live vaccine within 30 days prior to the first dose of trial treatment.&#xD;
             Examples of live vaccines include, but are not limited to: measles, mumps, rubella,&#xD;
             chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza&#xD;
             vaccines for injection are generally killed virus vaccines and are allowed; however,&#xD;
             intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are&#xD;
             not allowed.&#xD;
&#xD;
          -  History of blood clots, pulmonary embolism, or deep vein thrombosis unless on adequate&#xD;
             anticoagulant therapy as determined by the treating investigator (subject must be on&#xD;
             stable dose for 2 weeks) and all symptoms have resolved.&#xD;
&#xD;
          -  Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].&#xD;
&#xD;
          -  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
          -  Current use of immunosuppressive medication at time of study entry. The following are&#xD;
             exceptions to this exclusion criterion: intranasal, inhaled, topical steroids, or&#xD;
             local steroid injections (eg, intra-articular injection); steroids as premedication&#xD;
             for hypersensitivity reactions (eg, CT scan premedication). Cases requiring systemic&#xD;
             corticosteroids at physiologic doses must be discussed with Big Ten CRC and HiberCell&#xD;
             prior to enrollment.&#xD;
&#xD;
          -  Active autoimmune disease that might deteriorate when receiving an immunostimulatory&#xD;
             agent. Exceptions include: patients with controlled diabetes type 1, controlled hypo-&#xD;
             or hyperthyroidism, resolved childhood asthma/atopy, vitiligo, or psoriasis not&#xD;
             requiring immunosuppressive treatment.&#xD;
&#xD;
          -  Received prior chemotherapy, an immune checkpoint inhibitor, or radiation therapy&#xD;
             within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1&#xD;
             or at baseline) from adverse events from previously administered agents. NOTE:&#xD;
             Subjects with alopecia, grade ≤ 2 sensory neuropathy or other grade ≤ 2 AEs not&#xD;
             constituting a safety risk based on investigator judgement are an exception to this&#xD;
             criterion and can still be considered for the study.&#xD;
&#xD;
          -  Any clinically significant infection requiring anti-infective treatment. Patients with&#xD;
             infection that is adequately treated will be eligible.&#xD;
&#xD;
          -  History of interstitial lung disease requiring immunosuppressive/steroids or history&#xD;
             of immunotherapy related pneumonitis that has required steroids or immunosuppression&#xD;
             in the past.&#xD;
&#xD;
          -  Known history of active tuberculosis.&#xD;
&#xD;
          -  Any other severe, uncontrolled medical condition, including uncontrolled diabetes&#xD;
             mellitus (defined as a Hemoglobin A1C ≥ 9% in subjects with a prior history of&#xD;
             diabetes, 28 days prior to study registration) or unstable congestive heart failure&#xD;
             (Stage III-IV of the New York Heart Association Functional Classification).&#xD;
&#xD;
          -  Previous known allergy or intolerance to pembrolizumab or any of its excipients.&#xD;
&#xD;
          -  Previous exposure or known allergy to Imprime PGG or any of its excipients.&#xD;
&#xD;
          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant&#xD;
             human antibodies.&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or&#xD;
             investigational product administration, interfere with protocol compliance, or may&#xD;
             interfere with the interpretation of study results and, in the judgment of the&#xD;
             investigator, would make the subject inappropriate for enrollment in this study.&#xD;
&#xD;
          -  Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study&#xD;
             registration.&#xD;
&#xD;
          -  Any mental or medical condition that prevents the subject from giving informed consent&#xD;
             or participating in the trial.&#xD;
&#xD;
          -  No prior malignancy is allowed except for adequately treated basal cell or squamous&#xD;
             cell skin cancer, in situ cervical cancer, in situ breast cancer, Gleason ≤ grade 7&#xD;
             prostate cancers, low grade papillary urothelial carcinoma or other cancer for which&#xD;
             the subject has been disease-free for at least 2 years. And no additional therapy&#xD;
             other than hormonal therapy is required for anticipated to be required during the&#xD;
             trial period.&#xD;
&#xD;
          -  Treatment with any therapeutic investigational agent within 28 days prior to study&#xD;
             registration.&#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>Lawrence Feldman, M.D.</last_name>
    <role>Study Chair</role>
    <affiliation>Big Ten Cancer Research Consortium</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Illinois at Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana Univeristy Melvin and Bren Simon Cancer Center</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospital and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Cancer Institute</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.bigtencrc.org</url>
    <description>Big Ten Cancer Research Consortium Website</description>
  </link>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>December 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <last_update_submitted>October 6, 2022</last_update_submitted>
  <last_update_submitted_qc>October 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Big Ten Cancer Research Consortium</investigator_affiliation>
    <investigator_full_name>Lawrence Feldman, MD</investigator_full_name>
    <investigator_title>M.D.</investigator_title>
  </responsible_party>
  <keyword>Anti-PD-1</keyword>
  <keyword>Pembrolizumab</keyword>
  <keyword>Imprime PGG</keyword>
  <keyword>MK-3475</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03003468
org study id: BTCRC-LUN15-017
nct id: NCT03003468
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is an open label, multi-institutional, single arm study with a dose escalation phase Ib
      cohort, followed by a phase II cohort of pembrolizumab and Imprime PGG. No randomization or
      blinding is involved.
OUTLINE: This is a multi-center study.

      The phase Ib dose escalation will evaluate the combination of pembrolizumab and Imprime PGG
      for subjects with metastatic non-small cell lung cancer (NSCLC) after progression on
      first-line platinum-based chemotherapy. The phase II trial will test whether addition of
      Imprime PGG to pembrolizumab will increase median progression-free survival (PFS) in second
      line therapy setting in NSCLC.

      PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

      Cohort 1 will consist of 3-6 patients who will receive

        -  Imprime PGG 2 mg/kg IV on Days 1, 8, 15 for Cycles 1-4

        -  Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16

        -  Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

      Cohort 2 will consist of 3-6 patients who will receive

        -  Imprime PGG 4 mg/kg IV on Days 1, 8, 15 for Cycles 1-4

        -  Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16

        -  Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

      If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of
      therapy, an additional three subjects will be enrolled at dose level 2. If all subjects in
      dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be
      enrolled into dose level 2 to ensure only 0-1 of 6 subjects have a DLT. There will be no
      further escalation beyond dose level 2.

      PHASE II INVESTIGATIONAL TREATMENT:

      Pembrolizumab will be given on Day 1 of each 21 day cycle after Imprime PGG, and the RP2D
      dose of Imprime PGG will be given on Days 1, 8 and 15 of each 21 day cycle. Treatment will
      continue up to 16 cycles, or until disease progression, unacceptable toxicity, subject
      refusal, or subject death either from progression of disease, the therapy itself, or from
      other causes.

      Life expectancy: of 6 months or greater

      The following baseline labs must be completed within 28 days prior to registration for
      protocol therapy:

      Hepatic:

        -  total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
           subjects with total bilirubin levels > 1.5 x ULN (except subject with Gilbert's
           Syndrome, who can have total bilirubin < 3.0 mg/dl)

        -  aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
           hepatic metastases

        -  alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic
           metastases

      Renal:

        -  Serum creatinine ≤ 3 mg/dL OR

        -  if serum creatinine > 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min

      Hematopoietic:

        -  hemoglobin ≥ 9 g/dL, subjects requiring transfusion will not be eligible to start study

        -  and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

        -  and platelet count ≥ 100 × 10^9/L

      Coagulation:

        -  INR < 1.5 × ULN OR

        -  for subjects receiving anticoagulant, the subjects must, in the investigator's opinion,
           be clinically stable with no evidence of active bleeding while receiving anticoagulant
           therapy. The INR for subjects on warfarin should be in the therapeutic range. Low
           molecular weight heparin (LMWH) is allowed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: Open Label
measure: Phase Ib: Maximum Tolerated Dose
time frame: From the start of combination treatment until completion of the first cycle of treatment (21 days)
description: Phase Ib: Maximum tolerated dose (MTD) for subjects receiving Imprime PGG with pembrolizumab without experiencing dose-limiting toxicity(s) (DLT) per Common Terminology Criteria for Adverse Events (CTCAE) v4.
measure: Phase II: Progression Free Survival
time frame: From the date of enrollment until the criteria for disease progression is met as defined by RECIST 1.1 or death from any cause, whichever occurs first (up to 1 year from start of treatment)
description: Progression-free survival (PFS) with Imprime PGG and pembrolizumab combination therapy.
measure: Assess Adverse Effects
time frame: From start of treatment D1 and every treatment visit thereafter (up to 11 months [16 cycles])
description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability per Common Terminology Criteria for Adverse Events (CTCAE) v4.
measure: Clinical Benefit Ratio
time frame: From the start of treatment D1 assessed every 6 weeks +/- 1 week while on study treatment (up to 11 months [16 cycles])
description: Clinical Benefit Ratio (complete, partial response, or stable disease) as assessed per RECIST 1.1.
measure: Progression Free Survival (PFS) at 6 months
time frame: 6 months
description: Estimate Progression-Free Survival (PFS) and 6-month PFS using RECIST v1.1 in subjects with NSCLC when treated with Imprime PGG in combination with pembrolizumab who progressed after first-line systemic therapy.
measure: Overall Survival (OS)
time frame: from the start of the treatment until death from any cause (up to 1 year from start of treatment)
description: To determine the overall survival for this patient population at 1 year.
arm group label: Arm A - Phase Ib
arm group type: Experimental
description: Dose Escalation Cohort Cohort 1 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 of each 21 day cycle. Imprime PGG will be administered at 2mg/kg on Day 1,8, and 15 of cycles 1-4, and on Day 1 of cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.
Experimental: Arm A - Phase II Investigational Treatment The maximum safe dose of Imprime PGG in combination with pembrolizumab (as determined in the phase Ib cohort) will be given on Day 1,8, and 15 for cycles 1-4, and on Day 1 of cycles 5-16.
Cohort 2 will consist of 3-6 patients who will receive pembrolizumab 200mg IV on Day 1 and Imprime PGG at 4mg/kg on Day 1,8, and 15 for Cycles 1-4 and on Day 1 only for Cycles 5-16. On Day 1 of each cycle, the Imprime PGG intravenous infusion is given first followed 15-30 minutes later by the pembrolizumab.
intervention type: Drug
intervention name: Imprime PGG
description: Arm A: Phase Ib Cohort 1: 2mg/kg IV; Arm A: Phase Ib Cohort 2: 4mg/kg IV
arm group label: Arm A - Phase Ib
intervention type: Drug
intervention name: MK-3475
description: 200mg IV
arm group label: Arm A - Phase Ib
other name: pembrolizumab
other name: Keytruda
intervention type: Drug
intervention name: Imprime PGG
description: Arm B: Phase II treatment: administered at the maximum safe dose of 2mg or 4 mg as established in the Phase Ib cohort study.
arm group label: Arm A - Phase Ib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lawrence Feldman, M.D.
role: Study Chair
affiliation: Big Ten Cancer Research Consortium
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.bigtencrc.org
description: Big Ten Cancer Research Consortium Website
responsible party type: Sponsor-Investigator
investigator affiliation: Big Ten Cancer Research Consortium
investigator full name: Lawrence Feldman, MD
investigator title: M.D.
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Pembrolizumab
sharing ipd: No