<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/NCT03245021</url>
  </required_header>
  <id_info>
    <org_study_id>CA209-676</org_study_id>
    <nct_id>NCT03245021</nct_id>
  </id_info>
  <brief_title>Nivolumab Plus Rituximab in First-line Follicular Lymphoma gr 1-3A</brief_title>
  <acronym>1stFLOR</acronym>
  <official_title>First-line Treatment for Grade 1-3A Follicular Lymphoma Using Opdivo (Nivolumab) Plus Rituximab: The 1st FLOR Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dr. Eliza Hawkes</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Austin Health</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Firstline treatment for grade 13a Follicular Lymphoma using Opdivo (nivolumab) plus&#xD;
      Rituximab: The 1st FLOR trial&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will involve participants with a condition called Follicular NonHodgkin Lymphoma&#xD;
      (Follicular Lymphoma).&#xD;
&#xD;
      The main purpose of this study is to see if it is safe to give drug Nivolumab before and in&#xD;
      combination with drug Rituximab and to see how effective Nivolumab is in patients who have&#xD;
      had no previous drug treatment for their lymphoma. In particular, we will be monitoring for&#xD;
      any specific side effects which may be increased by adding Nivolumab to Rituximab treatment,&#xD;
      including monitoring of the immune system.&#xD;
&#xD;
      Participants will be reviewed at baseline and prior to each cycle of treatment for toxicity,&#xD;
      scans will be performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab&#xD;
      +/rituximab and at 6 months post induction treatment phase and following completion of&#xD;
      treatment, participants will be followed up for a total of 5 years (every 3 months for 2&#xD;
      years, every 6 months for 3 years). In participants with relapsed disease, these will be&#xD;
      followed for survival every 3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 7, 2017</start_date>
  <completion_date type="Anticipated">June 2027</completion_date>
  <primary_completion_date type="Actual">May 11, 2022</primary_completion_date>
  <phase>Phase 1</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>
    <intervention_model_description>Single Group Assignment</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To evaluate the feasibility and safety of combination nivolumab and rituximab as determined by the proportion of toxicity grade 3 or higher per CTCAE v4.0 occurring on induction treatment (ie first 16 weeks of therapy)</measure>
    <time_frame>1st 16 weeks of therapy</time_frame>
    <description>As determined by rate of toxicity grade 3 or higher per CTCAE v4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall toxicity</measure>
    <time_frame>5 years</time_frame>
    <description>As determined by rate of toxicity grade 3 or higher per CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate</measure>
    <time_frame>1st 16 weeks of therapy</time_frame>
    <description>Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete response rate</measure>
    <time_frame>6 months post completion of induction treatment</time_frame>
    <description>Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment failure</measure>
    <time_frame>5 years</time_frame>
    <description>Time to progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>5 years</time_frame>
    <description>Duration of survival without relapse or non-relapse mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>5 years</time_frame>
    <description>Overall toxicity as assessed by CTCAE v4.0</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">39</enrollment>
  <condition>Follicular Lymphoma</condition>
  <arm_group>
    <arm_group_label>Open-Label</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Opdivo - Single-arm open label study</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Opdivo</intervention_name>
    <description>All patients will receive:&#xD;
Nivolumab 240mg IV q2-weekly for four cycles&#xD;
Patients in complete remission (CR):&#xD;
Nivolumab 240mg IV q2-weekly for four further cycles (8 in total)&#xD;
Patients with partial response (PR), stable disease (SD), asymptomatic or minor progressive disease (PD) post 4cycles receive:&#xD;
Nivolumab 240mg IV plus rituximab 375mg/m2 IV q2-weekly for four cycles&#xD;
Patients in CR:&#xD;
Nivolumab 240mg IV q2-weekly for four further cycles (8 in total)&#xD;
Patients with PR, SD, asymptomatic or minor PD post 4 cycles receive:&#xD;
Nivolumab 240mg IV plus rituximab 375mg/m2 IV q2-weekly for four cycles</description>
    <arm_group_label>Open-Label</arm_group_label>
    <other_name>Rituximab</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years.&#xD;
&#xD;
          2. Histologically proven Follicular non Hodgkin lymphoma (FL) grades 1-3A according to&#xD;
             the current World Health Organization classification.29 The B cell nature of the&#xD;
             proliferation must be verified by the positivity with an anti-CD20 antibody.&#xD;
&#xD;
          3. No previous chemotherapy, or other investigational drug for this indication apart from&#xD;
             focal radiotherapy.&#xD;
&#xD;
          4. Stage II-IV disease (Ann Arbor criteria). Stage II disease must not be encompassable&#xD;
             in a single radiotherapy field and being considered for definitive radiotherapy.&#xD;
&#xD;
          5. Eastern Collaborative Oncology Group (ECOG) performance status 0 to 1 unless&#xD;
             attributable to lymphoma, in which case patients of performance status 2 are also&#xD;
             eligible.&#xD;
&#xD;
          6. Deemed to need treatment by treating investigator. Reasons for treatment can include,&#xD;
             but are not limited to:&#xD;
&#xD;
        a. Any nodal or extranodal tumour mass &gt;7cm AND/OR multiple extranodal disease sites b.&#xD;
        Involvement of at least 3 sites each with diameter &gt;3cm c. Symptomatic splenic enlargement&#xD;
        d. Organ involvement/compression e. Ascites or pleural effusion f. Lactate Dehydrogenase&#xD;
        (LDH) elevated g. Presence of systemic symptoms h. Disease progression in preceding 3&#xD;
        months i. Evidence of marrow infiltration with marrow compromise. (eg Hb, WBC or plt count&#xD;
        below lower limit of institutional normal range).&#xD;
&#xD;
        g) Adequate bone marrow function including:&#xD;
&#xD;
          1. Haemoglobin &gt;9.0 g/dL&#xD;
&#xD;
          2. White blood cells (WBC) ≥2000/μL&#xD;
&#xD;
          3. Neutrophils &gt;1.5 x 109/L&#xD;
&#xD;
          4. Platelets &gt;100 x 109/L at the time of study entry, unless attributed to bone marrow&#xD;
             infiltration by lymphoma.&#xD;
&#xD;
        h) Adequate renal function with serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl)&#xD;
        ≥ 40mL/min (using Cockroft-Gault formula) Female CrCl = (140 - age in years) x weight (kg)&#xD;
        x 0.85 72 x serum creatinine (mg/dL) Male CrCl = (140 - age in years) x weight (kg) x 1.00&#xD;
        72 x serum creatinine (mg/dL) i) Adequate hepatic function with AST/ALT ≤3x ULN and total&#xD;
        bilirubin ≤1.5 x ULN (except subjects with Gilbert syndrome, who can have a total bilirubin&#xD;
        ≤3 mg/dL or ≤51.3 μmol/L) j) Life expectancy &gt; 3 months. k) Patients of childbearing&#xD;
        potential willing to adhere to contraceptive precautions&#xD;
&#xD;
          1. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy&#xD;
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to&#xD;
             the start of study treatment&#xD;
&#xD;
          2. Women must not be breastfeeding&#xD;
&#xD;
          3. WOCBP must use appropriate method(s) of contraception to avoid pregnancy for 23 weeks&#xD;
             (30 days plus five half-lives of nivolumab) post-treatment completion&#xD;
&#xD;
          4. Men who are sexually active with WOCBP must use any contraceptive method with a&#xD;
             failure rate of less than 1% per year. They must agree to adhere to contraception for&#xD;
             a period of 31 weeks after the last day of nivolumab.&#xD;
&#xD;
          5. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt&#xD;
             from contraceptive requirements. However, they must still undergo pregnancy testing as&#xD;
             described in this section.&#xD;
&#xD;
        l) Written, informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Grade 3B follicular lymphoma, transformed follicular lymphoma, other indolent&#xD;
             lymphomas.&#xD;
&#xD;
          2. Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4&#xD;
             antibody or any other antibody or drug specifically targeting T-cell co-stimulation or&#xD;
             checkpoint pathways.&#xD;
&#xD;
          3. Central nervous system, meningeal involvement or cord compression by lymphoma.&#xD;
&#xD;
          4. Patients with active, known or suspected autoimmune disease. Patients with well&#xD;
             controlled type I diabetes mellitus, coeliac disease, residual hypothyroidism due to&#xD;
             autoimmune condition only requiring hormone replacement, vitiligo or psoriasis not&#xD;
             requiring systemic treatment, or other conditions not expected to recur in the absence&#xD;
             of an external trigger are permitted to enrol.&#xD;
&#xD;
          5. Subjects with a condition requiring systemic treatment with either corticosteroids (&gt;&#xD;
             10mg daily prednisone equivalents) or other immunosuppressive medications within 14&#xD;
             days of study drug administration. Inhaled or topical steroids, and adrenal&#xD;
             replacement doses &gt; 10 mg daily prednisone equivalents are permitted in the absence of&#xD;
             active autoimmune disease.&#xD;
&#xD;
          6. Past history of interstitial lung disease.&#xD;
&#xD;
          7. Prior malignancy active within the previous 3 years except for locally curable cancers&#xD;
             that have been apparently cured, such as basal or squamous cell skin cancer,&#xD;
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.&#xD;
&#xD;
          8. Any other serious active disease.&#xD;
&#xD;
          9. Any positive test result for hepatitis B or hepatitis C virus during screening&#xD;
             indicating acute or chronic infection.&#xD;
&#xD;
         10. Any positive test for human immunodeficiency virus (HIV) or known acquired&#xD;
             immunodeficiency syndrome (AIDS)&#xD;
&#xD;
         11. Any history of severe hypersensitivity reactions to other monoclonal antibodies. A&#xD;
             history of allergy or intolerance (unacceptable AEs) to study drug components or&#xD;
             Polysorbate-80-containing infusions&#xD;
&#xD;
         12. Medical or psychiatric conditions that compromise the patient's ability to give&#xD;
             informed consent.&#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>Eliza Hawkes, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Austin Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ballarat Health</name>
      <address>
        <city>Ballarat</city>
        <state>Victoria</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Eastern Health</name>
      <address>
        <city>Box Hill</city>
        <state>Victoria</state>
        <zip>3128</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Monash Health</name>
      <address>
        <city>Clayton</city>
        <state>Victoria</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Austin Health</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Vincent's Hospital</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>August 7, 2017</study_first_submitted>
  <study_first_submitted_qc>August 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2017</study_first_posted>
  <last_update_submitted>January 30, 2023</last_update_submitted>
  <last_update_submitted_qc>January 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Austin Health</investigator_affiliation>
    <investigator_full_name>Dr. Eliza Hawkes</investigator_full_name>
    <investigator_title>Chief Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Follicular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>IPD is the property of the Sponsor (Austin Health). Results from the research intends to be published/presented in relevant publications/conferences for colleague review</ipd_description>
  </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/NCT03245021
org study id: CA209-676
nct id: NCT03245021
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Firstline treatment for grade 13a Follicular Lymphoma using Opdivo (nivolumab) plus
      Rituximab: The 1st FLOR trial
This study will involve participants with a condition called Follicular NonHodgkin Lymphoma
      (Follicular Lymphoma).

      The main purpose of this study is to see if it is safe to give drug Nivolumab before and in
      combination with drug Rituximab and to see how effective Nivolumab is in patients who have
      had no previous drug treatment for their lymphoma. In particular, we will be monitoring for
      any specific side effects which may be increased by adding Nivolumab to Rituximab treatment,
      including monitoring of the immune system.

      Participants will be reviewed at baseline and prior to each cycle of treatment for toxicity,
      scans will be performed at baseline, after 4 cycles of nivolumab, after 8 cycles of nivolumab
      +/rituximab and at 6 months post induction treatment phase and following completion of
      treatment, participants will be followed up for a total of 5 years (every 3 months for 2
      years, every 6 months for 3 years). In participants with relapsed disease, these will be
      followed for survival every 3 months.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To evaluate the feasibility and safety of combination nivolumab and rituximab as determined by the proportion of toxicity grade 3 or higher per CTCAE v4.0 occurring on induction treatment (ie first 16 weeks of therapy)
time frame: 1st 16 weeks of therapy
description: As determined by rate of toxicity grade 3 or higher per CTCAE v4.0
measure: Overall toxicity
time frame: 5 years
description: As determined by rate of toxicity grade 3 or higher per CTCAE v4.0
measure: Response rate
time frame: 1st 16 weeks of therapy
description: Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
measure: Complete response rate
time frame: 6 months post completion of induction treatment
description: Response Rate to Nivolumab + Rituximab according to the Lugano classification for Response Criteria for Non-Hodgkin Lymphoma
measure: Time to treatment failure
time frame: 5 years
description: Time to progression
measure: Progression free survival
time frame: 5 years
description: Duration of survival without relapse or non-relapse mortality
measure: Overall survival
time frame: 5 years
description: Overall toxicity as assessed by CTCAE v4.0
arm group label: Open-Label
arm group type: Other
description: Opdivo - Single-arm open label study
intervention type: Drug
intervention name: Opdivo
description: All patients will receive:
Nivolumab 240mg IV q2-weekly for four cycles
Patients in complete remission (CR):
Nivolumab 240mg IV q2-weekly for four further cycles (8 in total)
Patients with partial response (PR), stable disease (SD), asymptomatic or minor progressive disease (PD) post 4cycles receive:
Nivolumab 240mg IV plus rituximab 375mg/m2 IV q2-weekly for four cycles
Patients in CR:
Nivolumab 240mg IV q2-weekly for four further cycles (8 in total)
Patients with PR, SD, asymptomatic or minor PD post 4 cycles receive:
Nivolumab 240mg IV plus rituximab 375mg/m2 IV q2-weekly for four cycles
arm group label: Open-Label
other name: Rituximab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Eliza Hawkes, MD
role: Principal Investigator
affiliation: Austin Health
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
responsible party type: Sponsor-Investigator
investigator affiliation: Austin Health
investigator full name: Dr. Eliza Hawkes
investigator title: Chief Principal Investigator
mesh term: Lymphoma
mesh term: Lymphoma, Follicular
mesh term: Rituximab
mesh term: Nivolumab
sharing ipd: Undecided
ipd description: IPD is the property of the Sponsor (Austin Health). Results from the research intends to be published/presented in relevant publications/conferences for colleague review