<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/NCT04493203</url>
  </required_header>
  <id_info>
    <org_study_id>20-101</org_study_id>
    <nct_id>NCT04493203</nct_id>
  </id_info>
  <brief_title>Nivolumab Plus Axitinib in Patients With Anti-PD1 Refractory Advanced Melanoma</brief_title>
  <official_title>A Phase II Trial of Nivolumab Plus Axitinib in Patients With Anti-PD1 Refractory Advanced Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yana Najjar</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is Phase II trial of nivolumab plus axitinib for patients with unresectable stage III or&#xD;
      IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant&#xD;
      anti-CTLA4 therapy. Patients will receive treatment with nivolumab 480 mg intravenously every&#xD;
      4 weeks and axitinib 5 mg twice daily by mouth. Patients may continue both agents for up to&#xD;
      two years if they do not experience disease progression or dose-limiting toxicities.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This trial hypothesizes that decreasing hypoxia in the TME will re-sensitize melanoma tumors&#xD;
      to anti-PD1 therapy. Axitinib has already been safely combined with anti-PD1 therapy and was&#xD;
      overall well-tolerated. With nivolumab plus axitinib taken together, based on previously&#xD;
      published work and data from our laboratories, it is hypothesized that axitinib can&#xD;
      metabolically remodel the TME to render it more sensitive to ICB, specifically by reducing&#xD;
      intra-tumoral hypoxia, increasing T cell infiltration, and increasing polyfunctional T cells.&#xD;
      It will determined if treatment with nivolumab plus axitinib will prolong both&#xD;
      progression-free and overall survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 18, 2020</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">September 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>Up to 12 weeks from baseline (after treatment)</time_frame>
    <description>Overall response rate (ORR) will be estimated by the percentage of patients who achieve Complete Response (CR) or Partial Response (PR) as best response by RECIST v1.1 criteria (with exact 95% CI). Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serious Adverse Events Possibly, Probably or Definitely Related to Study Treatment</measure>
    <time_frame>Up to 28 days after discontinuation of study treatment</time_frame>
    <description>Frequency of patients experiencing Serious Adverse Events determined to be possibly, probably or definitely related to study treatment using a Bayesian monitoring scheme to continuously monitor the rate of severe adverse events (SAE). SAEs are defined as grade 3 and higher toxicity events that are attributable to the study combination therapy. Toxicity events will evaluated by NCI Common Terminology for Adverse Events (CTCAE v5.0).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Progression-free survival is the time measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression), whichever occurs first, with progression defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The length of time from the start of treatment that patients remain alive, until death from any cause.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">31</enrollment>
  <condition>Advanced Melanoma</condition>
  <condition>Unresectable Melanoma</condition>
  <arm_group>
    <arm_group_label>Nivolumab plus Axitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 480mg, IV, every 4 weeks, for up to two years.&#xD;
Axitinib 5mg, PO, BID, for up to two years.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1. It is a type of Immunotherapy and works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer.</description>
    <arm_group_label>Nivolumab plus Axitinib</arm_group_label>
    <other_name>Opdivo</other_name>
    <other_name>AG013736</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Axitinib</intervention_name>
    <description>Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor.Its primary mechanism of action is thought to be vascular endothelial growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours)</description>
    <arm_group_label>Nivolumab plus Axitinib</arm_group_label>
    <other_name>INLYTA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Have unresectable (stage III) or advanced (stage IV) cutaneous or mucosal melanoma.&#xD;
             Patients with uveal melanoma are not eligible.&#xD;
&#xD;
          -  Progressed on prior anti-PD1 therapy with or without anti-CTLA4 therapy. Patients may&#xD;
             have progressed in the adjuvant setting if treated within the last 6 months. Prior&#xD;
             treatment with BRAF/MEK inhibitors permitted, however, not required. Progression must&#xD;
             be radiographic, and progression of disease will be confirmed by a radiologist.&#xD;
             Patients must have progressed during anti-PD-1 therapy, defined as unequivocal&#xD;
             progression on or within 3 months of the last dose of anti-PD-1 therapy if treated in&#xD;
             the metastatic setting, or within 6 months if treated in the adjuvant setting.&#xD;
&#xD;
          -  Have measurable disease based on RECIST 1.1.&#xD;
&#xD;
          -  Patients do not have to have biopsiable disease to be eligible. However, patients with&#xD;
             biopsiable disease must undergo biopsy at study entry and at week 12.&#xD;
&#xD;
          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.&#xD;
&#xD;
          -  Demonstrate adequate organ function, per protocol&#xD;
&#xD;
          -  Patients with brain metastases are permitted if they are asymptomatic or previously&#xD;
             treated with CNS directed therapy with stable CNS disease for at least 2 weeks. Stable&#xD;
             is defined as asymptomatic or not progressing on imaging.&#xD;
&#xD;
          -  Female patients of childbearing potential - negative pregnancy testing; use of birth&#xD;
             control, surgically sterile or abstain from heterosexual activity during study and for&#xD;
             5 months after the last dose of study medication.&#xD;
&#xD;
          -  Male subjects - agree to use an adequate contraception starting with the first dose of&#xD;
             study therapy through 7 months after the last dose of study therapy; abstinence&#xD;
             acceptable&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior history of Grade 3 or 4 immune-related adverse events or immune-related adverse&#xD;
             events requiring discontinuation of prior therapies.&#xD;
&#xD;
          -  History of hypertensive crisis or hypertensive encephalopathy.&#xD;
&#xD;
          -  Significant thrombotic (e.g. deep vein thrombosis or pulmonary embolism) or&#xD;
             hemorrhagic event within 6 months prior to enrollment.&#xD;
&#xD;
          -  History of prior immune-related adverse event due to an anti-PD1 or anti-CTLA4 that&#xD;
             has not resolved to grade 1 on a steroid dose of prednisone 10 mg or less at the time&#xD;
             of study entry (excluding vitiligo and endocrine toxicity).&#xD;
&#xD;
          -  Patients with prior myocarditis or other immune-mediated cardiac adverse events, prior&#xD;
             Guillain-Barre syndrome, encephalitis, meningitis, or transverse myelitis, prior&#xD;
             Stevens-Johnson syndrome or toxic epidermal necrolysis are excluded regardless of&#xD;
             grade.&#xD;
&#xD;
          -  Poorly controlled hypertension defined as systolic blood pressure (SBP) &gt; 160 and/or&#xD;
             diastolic blood pressure (DBP) &gt; 100 despite antihypertensives. If subject is above&#xD;
             this goal, treatment with anti-hypertensives to achieve better blood pressure control&#xD;
             is permitted. Ambulatory blood pressure assessment is permitted if there is concern&#xD;
             for discrepant blood pressure readings while patients are in clinic.&#xD;
&#xD;
          -  Has Class III or IV heart failure based on the New York Heart Association.&#xD;
&#xD;
          -  Has had major surgery within 4 weeks of randomization. This does not include&#xD;
             outpatient surgeries that do not require post-operative admission.&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (greater&#xD;
             than the equivalent of prednisone 10 mg daily, unless for prior endocrine toxicity) or&#xD;
             any other form of immunosuppressive therapy within 7 days prior to the first dose of&#xD;
             trial treatment (premedication with steroids for contrast imaging studies is&#xD;
             permitted).&#xD;
&#xD;
          -  Has a known history of active TB (Bacillus Tuberculosis).&#xD;
&#xD;
          -  Hypersensitivity to nivolumab or axitinib, or any of their excipients.&#xD;
&#xD;
          -  Has had prior chemotherapy or targeted small molecule therapy within 1 week prior to&#xD;
             study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse&#xD;
             events due to a previously administered agent.&#xD;
&#xD;
          -  Has had radiation within 2 weeks of randomization.&#xD;
&#xD;
          -  Has current use or anticipated need for treatment with drugs or foods that are known&#xD;
             strong cytochrome P450 (CYP34A4/5) inhibitors including but not limited to atazanavir,&#xD;
             clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir,&#xD;
             ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit or&#xD;
             grapefruit juice. NOTE: The topical use of these medications, such as 2% ketoconazole&#xD;
             cream is allowed.&#xD;
&#xD;
          -  Has current use or anticipated need for treatment with drugs known to be strong&#xD;
             CYP3A4/5 inducers, including but not limited to carbamazepine, phenobarbital,&#xD;
             phenytoin, rifabutin, rifampin, and St. John's wort.&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy, in situ cervical cancer, in situ&#xD;
             colon cancer, or nonmetastatic prostate cancer not on systemic therapy.&#xD;
&#xD;
          -  Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis. Subjects with previously treated brain metastases may participate provided&#xD;
             they are stable (without evidence of progression by imaging for at least 2 weeks prior&#xD;
             to the first dose of trial treatment and any neurologic symptoms have returned to&#xD;
             baseline), have no evidence of new or enlarging brain metastases, and are not using&#xD;
             steroids for at least 7 days prior to trial treatment. This exception does not include&#xD;
             carcinomatous meningitis which is excluded regardless of clinical stability.&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement&#xD;
             therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of&#xD;
             systemic treatment.&#xD;
&#xD;
          -  Has a history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis.&#xD;
&#xD;
          -  Has an active infection requiring systemic IV antibiotic therapy.&#xD;
&#xD;
          -  Has had any of the following within the past 6 months&#xD;
&#xD;
          -  Myocardial infarction or unstable angina&#xD;
&#xD;
          -  Ventricular arrythmia&#xD;
&#xD;
          -  Acute decompensated heart failure&#xD;
&#xD;
          -  Cerebrovascular accident&#xD;
&#xD;
          -  Hypertensive emergency requiring ICU admission&#xD;
&#xD;
          -  Presence of a disorder that may impact absorption of axitinib, such as inability to&#xD;
             take oral medication, requirement for IV alimentation, prior gastric resection,&#xD;
             treatment for active peptic ulcer confirmed by endoscopy within the past 3 months,&#xD;
             active GI bleed, malabsorption syndrome.&#xD;
&#xD;
          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Is pregnant or breastfeeding or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 5 months after the last dose of trial treatment for females and 7 months after&#xD;
             the last dose of trial treatment for males.&#xD;
&#xD;
          -  Has a known history of HIV (HIV 1/2 antibodies) if the CD4 count is less than 350 mm3&#xD;
             or serum HIV viral load is &lt; 25,000 IU/mL.&#xD;
&#xD;
          -  Has a known history of or is positive for hepatitis B (hepatitis B surface antigen&#xD;
             [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is&#xD;
             detected). Note: Without known history, testing only needs to be performed if there is&#xD;
             clinical suspicion for Hepatitis B or C.&#xD;
&#xD;
          -  Is currently incarcerated or otherwise detained.&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy.&#xD;
             (intranasal iNinfluenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and&#xD;
             are not allowed)&#xD;
&#xD;
        Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify&#xD;
        for the study.&#xD;
&#xD;
        Note: If subject received major surgery, they must have recovered adequately from the&#xD;
        toxicity and/or complications from the intervention prior to starting therapy.&#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>Yana Najjar, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UPMC Hillman Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Amy Rose, RN</last_name>
    <phone>412-647-8587</phone>
    <email>kennaj@upmc.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amy Rose, RN, BSN</last_name>
      <phone>412-647-8587</phone>
      <email>kennaj@upmc.edu</email>
    </contact>
    <investigator>
      <last_name>Yana Najjar, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>April 13, 2023</last_update_submitted>
  <last_update_submitted_qc>April 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Yana Najjar</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Axitinib</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/NCT04493203
org study id: 20-101
nct id: NCT04493203
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is Phase II trial of nivolumab plus axitinib for patients with unresectable stage III or
      IV melanoma who have progressed on prior anti-PD1 therapy with or without concomitant
      anti-CTLA4 therapy. Patients will receive treatment with nivolumab 480 mg intravenously every
      4 weeks and axitinib 5 mg twice daily by mouth. Patients may continue both agents for up to
      two years if they do not experience disease progression or dose-limiting toxicities.
This trial hypothesizes that decreasing hypoxia in the TME will re-sensitize melanoma tumors
      to anti-PD1 therapy. Axitinib has already been safely combined with anti-PD1 therapy and was
      overall well-tolerated. With nivolumab plus axitinib taken together, based on previously
      published work and data from our laboratories, it is hypothesized that axitinib can
      metabolically remodel the TME to render it more sensitive to ICB, specifically by reducing
      intra-tumoral hypoxia, increasing T cell infiltration, and increasing polyfunctional T cells.
      It will determined if treatment with nivolumab plus axitinib will prolong both
      progression-free and overall survival.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate (ORR)
time frame: Up to 12 weeks from baseline (after treatment)
description: Overall response rate (ORR) will be estimated by the percentage of patients who achieve Complete Response (CR) or Partial Response (PR) as best response by RECIST v1.1 criteria (with exact 95% CI). Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.
measure: Serious Adverse Events Possibly, Probably or Definitely Related to Study Treatment
time frame: Up to 28 days after discontinuation of study treatment
description: Frequency of patients experiencing Serious Adverse Events determined to be possibly, probably or definitely related to study treatment using a Bayesian monitoring scheme to continuously monitor the rate of severe adverse events (SAE). SAEs are defined as grade 3 and higher toxicity events that are attributable to the study combination therapy. Toxicity events will evaluated by NCI Common Terminology for Adverse Events (CTCAE v5.0).
measure: Progression-free Survival (PFS)
time frame: Up to 5 years
description: Progression-free survival is the time measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression), whichever occurs first, with progression defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions
measure: Overall Survival (OS)
time frame: Up to 5 years
description: The length of time from the start of treatment that patients remain alive, until death from any cause.
arm group label: Nivolumab plus Axitinib
arm group type: Experimental
description: Nivolumab 480mg, IV, every 4 weeks, for up to two years.
Axitinib 5mg, PO, BID, for up to two years.
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1. It is a type of Immunotherapy and works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer.
arm group label: Nivolumab plus Axitinib
other name: Opdivo
other name: AG013736
intervention type: Drug
intervention name: Axitinib
description: Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor.Its primary mechanism of action is thought to be vascular endothelial growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours)
arm group label: Nivolumab plus Axitinib
other name: INLYTA
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Yana Najjar, MD
role: Principal Investigator
affiliation: UPMC Hillman Cancer Center
last name: Amy Rose, RN
phone: 412-647-8587
email: kennaj@upmc.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Yana Najjar
investigator title: Assistant Professor
mesh term: Melanoma
mesh term: Nivolumab
mesh term: Axitinib
sharing ipd: No