<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/NCT03298893</url>
  </required_header>
  <id_info>
    <org_study_id>IC 2016-08</org_study_id>
    <nct_id>NCT03298893</nct_id>
  </id_info>
  <brief_title>Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months</brief_title>
  <acronym>NiCOL</acronym>
  <official_title>A Phase-I Study of Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months. NiCOL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Curie</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut Curie</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as&#xD;
      monotherapy, and the next logical step is to evaluate rational therapeutic associations. The&#xD;
      aim of the NiCOL study is to assess the safety of nivolumab in association with&#xD;
      chemoradiation therapy and to gain initial insight into its efficacy in association with the&#xD;
      current standard of care, including chemoradiation.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 27, 2017</start_date>
  <completion_date type="Actual">March 7, 2022</completion_date>
  <primary_completion_date type="Actual">October 30, 2020</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>
  </study_design_info>
  <primary_outcome>
    <measure>rate of occurrence of dose-limiting toxicity (DLT)</measure>
    <time_frame>within 11 weeks after the initiation of treatment.</time_frame>
    <description>DLT is defined as any of the following treatment-related adverse events or laboratory abnormalities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0:&#xD;
non-hematological toxicity ≥ grade 3;&#xD;
immune-related adverse event ≥ grade 3;&#xD;
symptomatic immune-related adverse event ≥ grade 2 resistant to optimal supportive care for &gt; 7 days;&#xD;
dosing delay in RT ≥ 1 week due to toxicity related to nivolumab, chemotherapy or RT;&#xD;
colitis or diarrhea ≥ grade 3.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>after the end of RT and before brachytherapy and again up to 2 months after brachytherapy</time_frame>
    <description>ORR is defined as the proportion of all subjects whose best response is either a complete response or a partial response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>2 years</time_frame>
    <description>PFS is defined as the length of time from the start of treatment to disease progression or death, regardless of the cause of death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Free Survival (DFS)</measure>
    <time_frame>2 years</time_frame>
    <description>DFS is defined as the length of time from the start of complete response to the time of relapse from complete response. DFS applies only to patients in complete response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Serious Adverse Events (SAEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy</measure>
    <time_frame>from the first intake of the IMP until 100 days after the last intake of the IMP</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events (AEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy</measure>
    <time_frame>from the first intake of the IMP until 100 days after the last intake of the IMP</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>validation of molecular alterations detected by molecular analyses</measure>
    <time_frame>2 years</time_frame>
    <description>Retrospective exome, RNA and targeted sequencing analyses will be performed on all patients treated and for whom tumor samples are available.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ctDNA heterogeneity</measure>
    <time_frame>baseline, at Weeks 3, 6 and 12 and every 12 weeks up to Week 104</time_frame>
    <description>Retrospective exome and targeted sequencing analyses will be performed on all patients treated and for whom tissue samples are available at the different timepoints</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tumor microenvironment description</measure>
    <time_frame>2 years</time_frame>
    <description>phenotypic analysis of the different components of the tumor microenvironment using various technologies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>tumor PD-L1 immunohistochemistry</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Cervical Cancer</condition>
  <condition>Locally Advanced Cervical Cancer</condition>
  <arm_group>
    <arm_group_label>Nivolumab + radiochemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab Injection</intervention_name>
    <description>2 possible doses : flat dose 240 mg q2 weeks or 1mg/kg q2 weeks</description>
    <arm_group_label>Nivolumab + radiochemotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>40 mg/m2, once a week during radiotherapy</description>
    <arm_group_label>Nivolumab + radiochemotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>radiotherapy</intervention_name>
    <description>Intensity-modulated radiation therapy (including volumetric-modulated arc therapy and tomography) will be used. A dose of 45 Gy will be delivered to the pelvis in 25 fractions of 1.8 Gy using a 6-MV photon energy.&#xD;
An additional dose of 54 Gy in 25 fractions of 2.16 Gy may be delivered to invaded lymph nodes using SIB-IMRT.&#xD;
An additional lateral pelvic dose may be delivered if coverage of the target volumes is judged insufficient. The volumes, doses and techniques will be those usually used in each center.</description>
    <arm_group_label>Nivolumab + radiochemotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients at least 18 years of age;&#xD;
&#xD;
          2. Ability to understand and the willingness to sign a written informed consent&#xD;
             document.;&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;&#xD;
&#xD;
          4. Histologically confirmed locally advanced cervical cancer, i.e. FIGO stages IB2 to&#xD;
             IVA, squamous-cell carcinoma or adenocarcinoma, with indication for radiotherapy and&#xD;
             cisplatin-based chemotherapy with a curative intent as confirmed by a&#xD;
             multidisciplinary board including a radiation oncologist. PD-L1 expression on tumor&#xD;
             will not be required for inclusion; (staging may include [18F]-fluorodeoxyglucose&#xD;
             (FDG) PET-CT and/or para-aortic dissection in accordance with usual practice in each&#xD;
             investigational center and at the Investigator's discretion);&#xD;
&#xD;
          5. Disease amenable to biopsy since three tumor samples are mandatory prior to treatment;&#xD;
&#xD;
          6. Laboratory values at Screening must meet the following criteria :&#xD;
&#xD;
             neutrophils ≥ 1.0 x 109/L, lymphocytes ≥ 0.5 x 109/L, platelets ≥ 100 x 109/L,&#xD;
             hemoglobin ≥ 8.0 g/dL, creatinine ≤ 2 times the upper limit of normal (ULN), aspartate&#xD;
             aminotransferase (AST) ≤ 3 ULN, alanine aminotransferase (ALT) ≤ 3 x ULN, total&#xD;
             bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if genetically documented Gilbert's syndrome).&#xD;
&#xD;
          7. For women with child-bearing potential, negative blood or urinary pregnancy test&#xD;
             within 24 hours of initiation of nivolumab, as well as appropriate method of&#xD;
             contraception throughout the study ;&#xD;
&#xD;
          8. Affiliated to the French Social Security System.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Metastases (except pelvic and/or para-aortic nodal metastases) ;&#xD;
&#xD;
          2. Peritoneal carcinosis;&#xD;
&#xD;
          3. Sensory or motor neuropathy ≥ grade 2;&#xD;
&#xD;
          4. Active or recent history of known autoimmune disease or recent history of a syndrome&#xD;
             that required systemic corticosteroids or immunosuppressive drugs, except for :&#xD;
&#xD;
               -  hydrocortisone, which is permitted at physiological doses;&#xD;
&#xD;
               -  syndromes that would not be expected to recur in the absence of an external&#xD;
                  trigger, e.g. glomerulonephritis;&#xD;
&#xD;
               -  vitiligo or autoimmune thyroiditis;&#xD;
&#xD;
          5. Type-1 or type-2 diabetes;&#xD;
&#xD;
          6. History of or current immunodeficiency disease, including known history of infection&#xD;
             with human immunodeficiency virus;&#xD;
&#xD;
          7. Prior systemic treatment or radiotherapy for cervical cancer;&#xD;
&#xD;
          8. Prior allogeneic stem cell transplantation;&#xD;
&#xD;
          9. Prior immunotherapy, including tumor vaccine, cytokine, anti-CTLA4, anti-PD-1,&#xD;
             anti-PD-L1 or similar agents;&#xD;
&#xD;
         10. Any non-oncologic vaccine for prevention of infectious disease within 28 days prior to&#xD;
             inclusion, including but not limited to measles, mumps, rubella, chicken pox, yellow&#xD;
             fever, seasonal influenza, H1N1, rabies, BCG, and typhoid vaccine;&#xD;
&#xD;
         11. Positive serology for hepatitis B surface antigen;&#xD;
&#xD;
         12. Positive for hepatitis-C ribonucleic acid on polymerase chain reaction;&#xD;
&#xD;
         13. Active infection requiring therapy;&#xD;
&#xD;
         14. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced&#xD;
             pneumonitis, organizing pneumonia or evidence of active pneumonitis on chest CT-scan&#xD;
             at Screening;&#xD;
&#xD;
         15. History of malignancy (excepting non-melanoma skin cancer) unless complete remission&#xD;
             was achieved at least 3 years prior to inclusion and no additional therapy is required&#xD;
             or planned during the study;&#xD;
&#xD;
         16. Underlying medical condition that, in the Investigator's opinion, could render the&#xD;
             administration of the study treatment hazardous; additional severe and/or uncontrolled&#xD;
             concurrent disease;&#xD;
&#xD;
         17. Concomitant use of other investigational drugs;&#xD;
&#xD;
         18. Pregnancy or breastfeeding.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Emanuela Romano, MD</last_name>
    <role>Study Director</role>
    <affiliation>Institut Curie</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut Curie</name>
      <address>
        <city>Paris</city>
        <zip>75005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Européen Georges Pompidou</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Curie Hopital René Huguenin</name>
      <address>
        <city>Saint Cloud</city>
        <zip>9220</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>September 27, 2017</study_first_submitted>
  <study_first_submitted_qc>September 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 2, 2017</study_first_posted>
  <last_update_submitted>April 28, 2022</last_update_submitted>
  <last_update_submitted_qc>April 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>cervical cancer</keyword>
  <keyword>nivolumab</keyword>
  <keyword>cisplatin</keyword>
  <keyword>radiotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Uterine Cervical Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03298893
org study id: IC 2016-08
nct id: NCT03298893
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as
      monotherapy, and the next logical step is to evaluate rational therapeutic associations. The
      aim of the NiCOL study is to assess the safety of nivolumab in association with
      chemoradiation therapy and to gain initial insight into its efficacy in association with the
      current standard of care, including chemoradiation.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: rate of occurrence of dose-limiting toxicity (DLT)
time frame: within 11 weeks after the initiation of treatment.
description: DLT is defined as any of the following treatment-related adverse events or laboratory abnormalities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0:
non-hematological toxicity ≥ grade 3;
immune-related adverse event ≥ grade 3;
symptomatic immune-related adverse event ≥ grade 2 resistant to optimal supportive care for > 7 days;
dosing delay in RT ≥ 1 week due to toxicity related to nivolumab, chemotherapy or RT;
colitis or diarrhea ≥ grade 3.
measure: Objective Response Rate (ORR)
time frame: after the end of RT and before brachytherapy and again up to 2 months after brachytherapy
description: ORR is defined as the proportion of all subjects whose best response is either a complete response or a partial response.
measure: Progression Free Survival (PFS)
time frame: 2 years
description: PFS is defined as the length of time from the start of treatment to disease progression or death, regardless of the cause of death
measure: Disease Free Survival (DFS)
time frame: 2 years
description: DFS is defined as the length of time from the start of complete response to the time of relapse from complete response. DFS applies only to patients in complete response.
measure: Incidence of Serious Adverse Events (SAEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy
time frame: from the first intake of the IMP until 100 days after the last intake of the IMP
measure: Incidence of Adverse Events (AEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy
time frame: from the first intake of the IMP until 100 days after the last intake of the IMP
measure: validation of molecular alterations detected by molecular analyses
time frame: 2 years
description: Retrospective exome, RNA and targeted sequencing analyses will be performed on all patients treated and for whom tumor samples are available.
measure: ctDNA heterogeneity
time frame: baseline, at Weeks 3, 6 and 12 and every 12 weeks up to Week 104
description: Retrospective exome and targeted sequencing analyses will be performed on all patients treated and for whom tissue samples are available at the different timepoints
measure: tumor microenvironment description
time frame: 2 years
description: phenotypic analysis of the different components of the tumor microenvironment using various technologies
measure: tumor PD-L1 immunohistochemistry
time frame: 2 years
arm group label: Nivolumab + radiochemotherapy
arm group type: Experimental
description: 5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone
intervention type: Drug
intervention name: Nivolumab Injection
description: 2 possible doses : flat dose 240 mg q2 weeks or 1mg/kg q2 weeks
arm group label: Nivolumab + radiochemotherapy
intervention type: Drug
intervention name: Cisplatin
description: 40 mg/m2, once a week during radiotherapy
arm group label: Nivolumab + radiochemotherapy
intervention type: Radiation
intervention name: radiotherapy
description: Intensity-modulated radiation therapy (including volumetric-modulated arc therapy and tomography) will be used. A dose of 45 Gy will be delivered to the pelvis in 25 fractions of 1.8 Gy using a 6-MV photon energy.
An additional dose of 54 Gy in 25 fractions of 2.16 Gy may be delivered to invaded lymph nodes using SIB-IMRT.
An additional lateral pelvic dose may be delivered if coverage of the target volumes is judged insufficient. The volumes, doses and techniques will be those usually used in each center.
arm group label: Nivolumab + radiochemotherapy
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Emanuela Romano, MD
role: Study Director
affiliation: Institut Curie
facility: 
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Uterine Cervical Neoplasms
mesh term: Nivolumab