<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/NCT03827850</url>
  </required_header>
  <id_info>
    <org_study_id>Uni-Koeln-3254</org_study_id>
    <secondary_id>2018-000399-13</secondary_id>
    <nct_id>NCT03827850</nct_id>
  </id_info>
  <brief_title>FGFR Inhibitor in FGFR Dysregulated Cancer</brief_title>
  <acronym>FIND</acronym>
  <official_title>A Phase II Trial to Evaluate Efficacy and Safety of Erdafitinib in Patients With Advanced Non Small Cell Lung Carcinoma (NSCLC) Harboring Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations After Relapse of Standard Therapy.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lung Cancer Group Cologne</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lung Cancer Group Cologne</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the FIND trial, Non Small Cell Lung Carcinoma (NSCLC) patients with Fibroblast Growth&#xD;
      Factor Receptor (FGFR) genetic alteration will be treated with the selective FGFR1-4&#xD;
      inhibitor erdafitinib. Archival samples, fresh frozen tumor samples and blood for circulating&#xD;
      tumor DNA (ctDNA) will be collected before treatment. Patients will be treated until disease&#xD;
      progression or unacceptable toxicity. In case of progression, fresh frozen tumor biopsies and&#xD;
      ctDNA analyses will be performed to assess resistance mechanisms. The primary objective of&#xD;
      the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic&#xD;
      alterations. NSCLC patient number will be based on a statistical hypothesis aiming at&#xD;
      increasing the response rate comparing to chemotherapy/immunotherapy after standard&#xD;
      treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Downstream signaling of fibroblast growth factor receptors 1-4 (FGFR 1-4) regulates cell&#xD;
      proliferation, migration, differentiation and survival in healthy cells. Genetic alterations&#xD;
      (amplifications, point-mutations and translocations) in FGFR1-4 genes cause altered signaling&#xD;
      and oncogenic transformation. FGFR-alterations with sensitivity to kinase inhibition have&#xD;
      been identified in a variety of tumors such as breast-, bladder- and endometrial-cancer,&#xD;
      squamous cell lung and head and neck cancer, cholangiocarcinoma and glioblastoma.&#xD;
&#xD;
      First-in-man/phase-I clinical trials with erdafitinib and BGJ398 - both selective FGFR&#xD;
      inhibitors - enrolled patients with any genetic alterations in FGFR. The trials showed&#xD;
      clinical responses with differences according to the type of FGFR alterations and&#xD;
      histological subtypes. In the BGJ398 trial, the partial response rate was 11% (4/36) in&#xD;
      patients with FGFR1 amplified squamous NSCLC (sqNSCLC) and 38% (3/8) in patients with&#xD;
      FGFR3-mutant bladder cancer. No PR was observed in patients with FGFR1/2 amplified (n=25) and&#xD;
      FGFR3 mutant (n=1) breast cancer. All patients with FGFR2-translocated (n=2) and&#xD;
      FGFR2-mutated cholangiocarcinoma (n=1) showed reduced tumor burden of 20% and 10%,&#xD;
      respectively. In the erdafitinib trial, 5 partial responses were seen in FGFR translocated&#xD;
      tumors: 3/8 (37.5%) patients with urothelial carcinoma, 1/3 (33%) patients with glioblastoma&#xD;
      and 1 patient with endometrial cancer reached PR. Summing up the results of the phase-I&#xD;
      trials, the inhibition of FGFR downstream pathways in FGFR translocated and mutated solid&#xD;
      tumors exerted clinical activity. Thus, focusing treatment with FGFR inhibitors on FGFR&#xD;
      mutated and translocated solid tumors may increase response rates, progression free and&#xD;
      overall survival in these tumors with otherwise adverse prognosis.&#xD;
&#xD;
      In NSCLC patients without druggable alterations in genes as EGFR, ALK or ROS1 and without&#xD;
      high PD-L1 (Programmed cell death 1 ligand 1) expression, prognosis remains adverse with a&#xD;
      median survival time of about 18 months. Particularly in sqNSCLC, only few driver mutations&#xD;
      have been identified yet. Of these, solely mutations of the KRAS gene (although observed at&#xD;
      low frequency in sqNSCLC) were explored in large clinical studies targeting KRAS downstream&#xD;
      signaling with no survival benefit comparing to chemotherapy. Immunotherapy with PD-1&#xD;
      antibodies such as nivolumab and pembrolizumab showed benefit in patients with high PD-L1&#xD;
      expression mainly.&#xD;
&#xD;
      The frequency of somatic FGFR1-3 mutations in lung cancer is about 4% (Helsten et al., 2016).&#xD;
      Translocations occur with a similar frequency of about 4% in lung cancer. Multiple of these&#xD;
      FGFR alterations are shown to have oncogenic potential as demonstrated in multiple in vitro,&#xD;
      in vivo and first-in-man studies.&#xD;
&#xD;
      Preclinical models in NSCLC cell lines and xenografts showed oncogenic activity of FGFR2/3&#xD;
      mutations with consecutive sensitivity to FGFR inhibitors. Similarly, FGFR3-TACC&#xD;
      translocation exerted kinase activation in sqNSCLC cell lines and other tumor types.&#xD;
      Furthermore, patient derived FGFR3-fusion lung xenograft model showed responses to FGFR&#xD;
      targeted treatment.&#xD;
&#xD;
      In summary, on the basis of genetically and phenotypically validated cell-line panels, in&#xD;
      vivo and particularly on the basis of clinical data, there is strong evidence for a clinical&#xD;
      benefit from FGFR inhibition for patients with FGFR altered NSCLC.&#xD;
&#xD;
      The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC&#xD;
      patients with FGFR genetic alterations. NSCLC patient number will be based on a statistical&#xD;
      hypothesis aiming at increasing the response rate comparing to chemotherapy/immunotherapy&#xD;
      after standard treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study-related difficulties faced with patient enrolment, no safety-related reasons&#xD;
  </why_stopped>
  <start_date type="Actual">March 25, 2019</start_date>
  <completion_date type="Actual">October 14, 2022</completion_date>
  <primary_completion_date type="Actual">September 30, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients with NSCLC and FGFR alteration with high evidence on oncogenic transformation according to FIND molecular board will be included to cohort 1 (FGFR translocated NSCLC patients) and cohort 2 (FGFR mutated NSCLC patients). Patients with NSCLC and FGFR alterations without enough evidence (intermediate / low evidence according to FIND molecular tumor board) for recruitment into cohorts 1 or 2, will be treated in cohort 3. Overall response rate under Erdafitinib treatment will be the primary endpoint.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>3 years</time_frame>
    <description>Overall response rate (ORR) per RECIST 1.1 under erdafitinib treatment in sqNSCLC with genetic alteration in FGFR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>number of adverse events per patient</measure>
    <time_frame>3 years</time_frame>
    <description>assessment of adverse events according to CTC-AE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>time length of progression free survival</measure>
    <time_frame>3 years</time_frame>
    <description>assessment of progression free survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>time length of overall survival</measure>
    <time_frame>3 years</time_frame>
    <description>assessment of overall survival</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Lung Cancer</condition>
  <condition>NSCLC</condition>
  <condition>Pulmonary Neoplasm</condition>
  <condition>Squamous Cell Lung Cancer</condition>
  <condition>NSCLC Stage IV</condition>
  <arm_group>
    <arm_group_label>Cohort 1 FGFR trans</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cohort 1: Activating (high confidence) FGFR translocations (max. 15 patients) under daily Erdaifitinib treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 FGFR mut</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cohort 2: Activating (high confidence) hotspot FGFR mutations (max. 15 patients) under daily Erdafitinib treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3 FGFR other</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cohort 3: Activating (low confidence) FGFR alteration (max. 20 patients)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ERDAFITINIB</intervention_name>
    <description>Daily in a range from 3 mg to 9 mg</description>
    <arm_group_label>Cohort 1 FGFR trans</arm_group_label>
    <arm_group_label>Cohort 2 FGFR mut</arm_group_label>
    <arm_group_label>Cohort 3 FGFR other</arm_group_label>
    <other_name>JNJ -42756493</other_name>
    <other_name>WHO NUMBER 10147</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Stage IIIB/IV NSCLC patients with activating FGFR alteration after the failure on any&#xD;
             prior line of standard treatment, or in the opinion of the investigator no effective&#xD;
             standard therapy exists, is appropriate, tolerated or is considered equivalent to&#xD;
             study treatment&#xD;
&#xD;
          -  Activating FGFR alteration as approved by FIND Molecular Board&#xD;
&#xD;
          -  Must sign an informed consent form (ICF) (or their legally acceptable representative&#xD;
             must sign) indicating that he or she understands the purpose of, and procedures&#xD;
             required for, the study and is willing to participate in the study.&#xD;
&#xD;
          -  ECOG performance status score 0, 1, or 2.&#xD;
&#xD;
          -  Clinical laboratory values and cardiovascular measurements at screening as defined in&#xD;
             protocol&#xD;
&#xD;
          -  Disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for&#xD;
             cohort 1 and 2. or evaluable disease.&#xD;
&#xD;
          -  A woman of childbearing potential who is sexually active must have a negative&#xD;
             pregnancy test (human chorionic gonadotropin [hCG]) at Screening (urine or serum,&#xD;
             minimum sensitivity 25 IU/L or equivalent units of b-HCG) within 24 hours prior to the&#xD;
             start of erdafitinib&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP&#xD;
             must use appropriate method(s) of contraception with a failure rate of less than 1%&#xD;
             per year before study entry, during the study and until 5 months after taking the last&#xD;
             dose of study drug. And other Criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pathogenic somatic alterations in the following genes: EGFR, BRAF, ALK, ROS1 and NTRK&#xD;
             (Please note that molecular testing might be reduced in heavy smokers with NSCLC)&#xD;
&#xD;
          -  Treatment with any other investigational agent or participation in another clinical&#xD;
             trial with therapeutic intent within 28 days prior to recruitment&#xD;
&#xD;
          -  Treatment with small molecules or chemotherapy within 7 days prior C1D1&#xD;
&#xD;
          -  Treatment with monoclonal antibodies within 28 days prior C1D1 if related to the&#xD;
             underlying malignancy&#xD;
&#xD;
          -  Any other history of ongoing malignancy that would potentially interfere with the&#xD;
             interpretation of erdafitinib efficacy&#xD;
&#xD;
          -  Symptomatic central nervous system metastases.&#xD;
&#xD;
          -  Received prior FGFR inhibitor treatment or if the patient has known allergies,&#xD;
             hypersensitivity, or intolerance to erdafitinib or its excipients&#xD;
&#xD;
          -  Any corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.:&#xD;
&#xD;
          -  History of or current evidence of CeSR or retinal vascular occlusion (RVO)&#xD;
&#xD;
          -  Active wet, age-related macular degeneration (AMD)&#xD;
&#xD;
          -  Diabetic retinopathy with macular edema (non-proliferative)&#xD;
&#xD;
          -  Uncontrolled glaucoma (per local standard of care)&#xD;
&#xD;
          -  Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal&#xD;
             abrasion, inflammation or ulceration.&#xD;
&#xD;
          -  Has persistent phosphate level &gt;ULN during screening (on 2 consecutive assessments at&#xD;
             least 1 week apart, within 14 days prior to Cycle 1 Day 1) and despite medical&#xD;
             management&#xD;
&#xD;
          -  Has a history of or current uncontrolled cardiovascular disease as defined in protocol&#xD;
&#xD;
          -  Known human immunodeficiency virus (HIV) infection, testing is mandatory (a-HIV 1/2)&#xD;
&#xD;
          -  Patients with acute or chronic Hepatitis B infection (tests should include assessment&#xD;
             of HBsAg and HBc IgG antibody. If one parameter is positive, determine HBV-DNA to&#xD;
             confirm acute infection. Patients with positive results for HBsAg and/or HBV-DNA are&#xD;
             considered positive for acute or chronic infection.&#xD;
&#xD;
          -  Patients with acute or chronic Hepatitis C infection (determine HCV-RNA. Patients with&#xD;
             positive result for HCV-RNA are considered positive for acute or chronic infection).&#xD;
&#xD;
          -  Has not recovered from reversible toxicity of prior anticancer therapy (except&#xD;
             toxicities which are not clinically significant such as alopecia, skin discoloration,&#xD;
             Grade 1 neuropathy, Grade 1-2 hearing loss)&#xD;
&#xD;
          -  Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg&#xD;
             ulcers, known gastric ulcers, or unhealed incisions&#xD;
&#xD;
          -  Major surgery within 2 weeks of the first dose, or will not have fully recovered from&#xD;
             surgery, or has surgery planned during the time the patient is expected to participate&#xD;
             in the study or within 2 weeks after the last dose of study drug administration.&#xD;
             (patients with planned surgical procedures to be conducted under local anesthesia may&#xD;
             participate).&#xD;
&#xD;
          -  Any serious underlying medical condition, such as:&#xD;
&#xD;
               -  Evidence of serious active viral, bacterial, or uncontrolled systemic fungal&#xD;
                  infection requiring current systemic treatment&#xD;
&#xD;
               -  Psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental&#xD;
                  status&#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>Lucia Nogova, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Clinic Cologne</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Asklepios Klinik München Gauting</name>
      <address>
        <city>Gauting</city>
        <state>Bavaria</state>
        <zip>82131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uniklinik Frankfurt</name>
      <address>
        <city>Frankfurt</city>
        <state>Hessen</state>
        <zip>60590</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Städtisches Klinikum Braunschweig</name>
      <address>
        <city>Braunschweig</city>
        <state>Niedersachsen</state>
        <zip>38114</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pius Hospital Oldenburg</name>
      <address>
        <city>Oldenburg</city>
        <state>Niedersachsen</state>
        <zip>26121</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uniklinik RWTH Aachen - Klinik für Hämotologie, Onkologie</name>
      <address>
        <city>Aachen</city>
        <state>NRW</state>
        <zip>52074</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Cologne</name>
      <address>
        <city>Cologne</city>
        <state>NRW</state>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Würzburg Comprehensive Cancer center</name>
      <address>
        <city>Würzburg</city>
        <state>NRW</state>
        <zip>97080</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uniklinik Carl Gustav Carus Dresden</name>
      <address>
        <city>Dresden</city>
        <state>Sachsen</state>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Evangelische Lungenklink Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>13125</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinik Freiburg</name>
      <address>
        <city>Freiburg</city>
        <zip>79106</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinik des Saarlandes Homburg</name>
      <address>
        <city>Homburg</city>
        <zip>66421</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, LoRusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol. 2017 Jan 10;35(2):157-165. doi: 10.1200/JCO.2016.67.2048. Epub 2016 Nov 21. Erratum In: J Clin Oncol. 2017 Mar 10;35(8):926. J Clin Oncol. 2019 Feb 1;37(4):358.</citation>
    <PMID>27870574</PMID>
  </reference>
  <reference>
    <citation>Hierro C, Rodon J, Tabernero J. Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors. Semin Oncol. 2015 Dec;42(6):801-19. doi: 10.1053/j.seminoncol.2015.09.027. Epub 2015 Sep 24.</citation>
    <PMID>26615127</PMID>
  </reference>
  <reference>
    <citation>Schildhaus HU, Nogova L, Wolf J, Buettner R. FGFR1 amplifications in squamous cell carcinomas of the lung: diagnostic and therapeutic implications. Transl Lung Cancer Res. 2013 Apr;2(2):92-100. doi: 10.3978/j.issn.2218-6751.2013.03.03.</citation>
    <PMID>25806220</PMID>
  </reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>June 7, 2023</last_update_submitted>
  <last_update_submitted_qc>June 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>sqNSCLC</keyword>
  <keyword>FGFR Mutations</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03827850
org study id: Uni-Koeln-3254
secondary id: 2018-000399-13
nct id: NCT03827850
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
In the FIND trial, Non Small Cell Lung Carcinoma (NSCLC) patients with Fibroblast Growth
      Factor Receptor (FGFR) genetic alteration will be treated with the selective FGFR1-4
      inhibitor erdafitinib. Archival samples, fresh frozen tumor samples and blood for circulating
      tumor DNA (ctDNA) will be collected before treatment. Patients will be treated until disease
      progression or unacceptable toxicity. In case of progression, fresh frozen tumor biopsies and
      ctDNA analyses will be performed to assess resistance mechanisms. The primary objective of
      the trial is to analyze the efficacy of erdafitinib in NSCLC patients with FGFR genetic
      alterations. NSCLC patient number will be based on a statistical hypothesis aiming at
      increasing the response rate comparing to chemotherapy/immunotherapy after standard
      treatment.
Downstream signaling of fibroblast growth factor receptors 1-4 (FGFR 1-4) regulates cell
      proliferation, migration, differentiation and survival in healthy cells. Genetic alterations
      (amplifications, point-mutations and translocations) in FGFR1-4 genes cause altered signaling
      and oncogenic transformation. FGFR-alterations with sensitivity to kinase inhibition have
      been identified in a variety of tumors such as breast-, bladder- and endometrial-cancer,
      squamous cell lung and head and neck cancer, cholangiocarcinoma and glioblastoma.

      First-in-man/phase-I clinical trials with erdafitinib and BGJ398 - both selective FGFR
      inhibitors - enrolled patients with any genetic alterations in FGFR. The trials showed
      clinical responses with differences according to the type of FGFR alterations and
      histological subtypes. In the BGJ398 trial, the partial response rate was 11% (4/36) in
      patients with FGFR1 amplified squamous NSCLC (sqNSCLC) and 38% (3/8) in patients with
      FGFR3-mutant bladder cancer. No PR was observed in patients with FGFR1/2 amplified (n=25) and
      FGFR3 mutant (n=1) breast cancer. All patients with FGFR2-translocated (n=2) and
      FGFR2-mutated cholangiocarcinoma (n=1) showed reduced tumor burden of 20% and 10%,
      respectively. In the erdafitinib trial, 5 partial responses were seen in FGFR translocated
      tumors: 3/8 (37.5%) patients with urothelial carcinoma, 1/3 (33%) patients with glioblastoma
      and 1 patient with endometrial cancer reached PR. Summing up the results of the phase-I
      trials, the inhibition of FGFR downstream pathways in FGFR translocated and mutated solid
      tumors exerted clinical activity. Thus, focusing treatment with FGFR inhibitors on FGFR
      mutated and translocated solid tumors may increase response rates, progression free and
      overall survival in these tumors with otherwise adverse prognosis.

      In NSCLC patients without druggable alterations in genes as EGFR, ALK or ROS1 and without
      high PD-L1 (Programmed cell death 1 ligand 1) expression, prognosis remains adverse with a
      median survival time of about 18 months. Particularly in sqNSCLC, only few driver mutations
      have been identified yet. Of these, solely mutations of the KRAS gene (although observed at
      low frequency in sqNSCLC) were explored in large clinical studies targeting KRAS downstream
      signaling with no survival benefit comparing to chemotherapy. Immunotherapy with PD-1
      antibodies such as nivolumab and pembrolizumab showed benefit in patients with high PD-L1
      expression mainly.

      The frequency of somatic FGFR1-3 mutations in lung cancer is about 4% (Helsten et al., 2016).
      Translocations occur with a similar frequency of about 4% in lung cancer. Multiple of these
      FGFR alterations are shown to have oncogenic potential as demonstrated in multiple in vitro,
      in vivo and first-in-man studies.

      Preclinical models in NSCLC cell lines and xenografts showed oncogenic activity of FGFR2/3
      mutations with consecutive sensitivity to FGFR inhibitors. Similarly, FGFR3-TACC
      translocation exerted kinase activation in sqNSCLC cell lines and other tumor types.
      Furthermore, patient derived FGFR3-fusion lung xenograft model showed responses to FGFR
      targeted treatment.

      In summary, on the basis of genetically and phenotypically validated cell-line panels, in
      vivo and particularly on the basis of clinical data, there is strong evidence for a clinical
      benefit from FGFR inhibition for patients with FGFR altered NSCLC.

      The primary objective of the trial is to analyze the efficacy of erdafitinib in NSCLC
      patients with FGFR genetic alterations. NSCLC patient number will be based on a statistical
      hypothesis aiming at increasing the response rate comparing to chemotherapy/immunotherapy
      after standard treatment.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Patients with NSCLC and FGFR alteration with high evidence on oncogenic transformation according to FIND molecular board will be included to cohort 1 (FGFR translocated NSCLC patients) and cohort 2 (FGFR mutated NSCLC patients). Patients with NSCLC and FGFR alterations without enough evidence (intermediate / low evidence according to FIND molecular tumor board) for recruitment into cohorts 1 or 2, will be treated in cohort 3. Overall response rate under Erdafitinib treatment will be the primary endpoint.
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate
time frame: 3 years
description: Overall response rate (ORR) per RECIST 1.1 under erdafitinib treatment in sqNSCLC with genetic alteration in FGFR
measure: number of adverse events per patient
time frame: 3 years
description: assessment of adverse events according to CTC-AE
measure: time length of progression free survival
time frame: 3 years
description: assessment of progression free survival
measure: time length of overall survival
time frame: 3 years
description: assessment of overall survival
arm group label: Cohort 1 FGFR trans
arm group type: Active Comparator
description: Cohort 1: Activating (high confidence) FGFR translocations (max. 15 patients) under daily Erdaifitinib treatment
arm group label: Cohort 2 FGFR mut
arm group type: Active Comparator
description: Cohort 2: Activating (high confidence) hotspot FGFR mutations (max. 15 patients) under daily Erdafitinib treatment
arm group label: Cohort 3 FGFR other
arm group type: Active Comparator
description: Cohort 3: Activating (low confidence) FGFR alteration (max. 20 patients)
intervention type: Drug
intervention name: ERDAFITINIB
description: Daily in a range from 3 mg to 9 mg
arm group label: Cohort 1 FGFR trans
arm group label: Cohort 2 FGFR mut
arm group label: Cohort 3 FGFR other
other name: JNJ -42756493
other name: WHO NUMBER 10147
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lucia Nogova, MD
role: Principal Investigator
affiliation: University Clinic Cologne
facility: 
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country: Germany
citation: Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, Cassier PA, Camidge DR, Schuler M, Vaishampayan U, Burris H, Tian GG, Campone M, Wainberg ZA, Lim WT, LoRusso P, Shapiro GI, Parker K, Chen X, Choudhury S, Ringeisen F, Graus-Porta D, Porter D, Isaacs R, Buettner R, Wolf J. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol. 2017 Jan 10;35(2):157-165. doi: 10.1200/JCO.2016.67.2048. Epub 2016 Nov 21. Erratum In: J Clin Oncol. 2017 Mar 10;35(8):926. J Clin Oncol. 2019 Feb 1;37(4):358.
PMID: 27870574
citation: Hierro C, Rodon J, Tabernero J. Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors. Semin Oncol. 2015 Dec;42(6):801-19. doi: 10.1053/j.seminoncol.2015.09.027. Epub 2015 Sep 24.
PMID: 26615127
citation: Schildhaus HU, Nogova L, Wolf J, Buettner R. FGFR1 amplifications in squamous cell carcinomas of the lung: diagnostic and therapeutic implications. Transl Lung Cancer Res. 2013 Apr;2(2):92-100. doi: 10.3978/j.issn.2218-6751.2013.03.03.
PMID: 25806220
responsible party type: Sponsor
mesh term: Lung Neoplasms
sharing ipd: Undecided