<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/NCT04424966</url>
  </required_header>
  <id_info>
    <org_study_id>2020-08</org_study_id>
    <secondary_id>20-500-092-34-38</secondary_id>
    <nct_id>NCT04424966</nct_id>
  </id_info>
  <brief_title>Infigratinib in Recurrent High-Grade Glioma Patients</brief_title>
  <official_title>A Phase 0 Study of Infigratinib in Recurrent High-Grade Glioma Participants Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With PK Triggered Expansion Cohort</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nader Sanai</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ivy Brain Tumor Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Barrow Neurological Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>QED Therapeutics</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>St. Joseph's Hospital and Medical Center, Phoenix</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This trial is an open-label, multicenter, Phase 0 trial that will enroll up to 20&#xD;
      participants with recurrent high-grade glioma with FGFR1 K656E or FGFR3 K650E mutation or&#xD;
      FGFR3-TACC3 translocation which are scheduled for resection. In the lead-in cohort, a total&#xD;
      of 20 participants will be enrolled into the proposed phase 0 clinical trial. Participants&#xD;
      will be administered infigratinib prior to surgical resection of their tumor.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study drug no longer available.&#xD;
  </why_stopped>
  <start_date type="Actual">July 21, 2020</start_date>
  <completion_date type="Actual">April 27, 2023</completion_date>
  <primary_completion_date type="Actual">April 27, 2023</primary_completion_date>
  <phase>Early 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase 0: Concentration of infigratinib in enhancing and non-enhancing tumor tissue</measure>
    <time_frame>Day 7 at 8 hours post dose</time_frame>
    <description>Phase 0: Tumor tissue will be collected approximately 8hrs after infigratinib administration on Day 7 to determine the concentration of infigratinib in the tumor tissue.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 0: Concentration of infigratinib in plasma (0-24H)</measure>
    <time_frame>Day 7 at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose</time_frame>
    <description>Samples will be collected at 8 timepoints during 24 hours after infigratinib administration on Day 7.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 0: Concentration of infigratinib in CSF</measure>
    <time_frame>Day 7 at 8 hours post dose</time_frame>
    <description>CSF will be collected at approximately 8hrs after infigratinib administration on Day 7 to determine the concentration of infigratinib in CSF.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Expansion Cohort: 6-month Progression-free survival</measure>
    <time_frame>6 months from the time of surgery</time_frame>
    <description>Expansion Cohort: 6-month Progression-free survival (PFS6) rate from time of surgery to date of recurrence</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase 0: PD Analysis</measure>
    <time_frame>Intraoperatively</time_frame>
    <description>Phase 0: percentage of pERK+, MIB-1+ and Cleaved Caspase 3+ cells from the surgical tissue will be quantified and compared to baseline archival tissue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse Events</measure>
    <time_frame>up to 30 days after the last study dose</time_frame>
    <description>Number of Adverse Events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of drug-related toxicity</measure>
    <time_frame>up to 30 days after the last study dose</time_frame>
    <description>Drug-related toxicity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of treatment-emergent adverse events</measure>
    <time_frame>up to 30 days after the last study dose</time_frame>
    <description>Treatment-emergent adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Deaths</measure>
    <time_frame>up to 60 months</time_frame>
    <description>Number and Incidence of Deaths</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of clinical laboratory abnormalities per CTCAE</measure>
    <time_frame>up to 30 days after the last study dose</time_frame>
    <description>Clinical laboratory abnormalities per CTCAE</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Glioma</condition>
  <condition>Glioblastoma</condition>
  <condition>GBM</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 0: 125 mg of infigratinib administered orally for 7 days prior to surgical resection.&#xD;
Expansion Cohort: 125 mg of infigratinib administered orally for 21 days of a 28-day treatment cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Infigratinib</intervention_name>
    <description>The Phase 0 study will include treatment of recurrent high-grade glioma participants with 125 mg of infigratinib 7 days prior to surgical resection. Participants with tumors demonstrating PK-response will continue treatment with the same dose continuously for 21 days in 28-day cycles after surgery.</description>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Prior resection of histologically diagnosed high-grade gliomas (III and IV) defined as&#xD;
             participants who have progressed on or following standard (Stupp regimen) therapy,&#xD;
             which included maximal surgical resection, temozolomide, and fractionated&#xD;
             radiotherapy.&#xD;
&#xD;
          2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or&#xD;
             contrast-enhanced MRI.&#xD;
&#xD;
          3. Have measurable disease preoperatively, defined as at least 1 contrast-enhancing&#xD;
             lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria.&#xD;
&#xD;
          4. Sufficient archival tissue available to confirm eligibility.&#xD;
&#xD;
          5. Archival tissue must demonstrate: FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3&#xD;
             translocation from NGS sequencing or IHC and RT-PCR.&#xD;
&#xD;
          6. Ability to understand and the willingness to sign a written informed consent document&#xD;
             (personally or by the legally authorized representative, if applicable).&#xD;
&#xD;
          7. Has voluntarily agreed to participate by giving written informed consent (personally&#xD;
             or via legally authorized representative(s), and assent if applicable). Written&#xD;
             informed consent for the protocol must be obtained prior to any screening procedures.&#xD;
             If consent cannot be expressed in writing, it must be formally documented and&#xD;
             witnessed, ideally via an independent trusted witness.&#xD;
&#xD;
          8. Willingness and ability to comply with scheduled visits, treatment plans, laboratory&#xD;
             tests and other procedures.&#xD;
&#xD;
          9. Age ≥18 at time of consent&#xD;
&#xD;
         10. Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG)&#xD;
             scale (Oken et al. 1982)&#xD;
&#xD;
         11. Ability to swallow oral medications.&#xD;
&#xD;
         12. Has adequate bone marrow and organ function as defined by the following laboratory&#xD;
             values (as assessed by the local laboratory for eligibility):&#xD;
&#xD;
               1. Adequate bone marrow function:&#xD;
&#xD;
                    -  absolute neutrophil count ≥1,000/mcL&#xD;
&#xD;
                    -  Platelets (at time of surgery) ≥100,000/mcL&#xD;
&#xD;
                    -  hemoglobin ≥8.0 g/dL Participants may receive erythrocyte transfusions to&#xD;
                       achieve this hemoglobin level at the discretion of the investigator.&#xD;
&#xD;
               2. Adequate hepatic and renal function:&#xD;
&#xD;
                    -  total bilirubin ≤1.5 X ULN Participants with Gilbert's syndrome with a total&#xD;
                       bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are&#xD;
                       permitted.&#xD;
&#xD;
                    -  AST(SGOT) ≤3 X institutional ULN&#xD;
&#xD;
                    -  ALT(SGPT) ≤3 X institutional ULN&#xD;
&#xD;
                    -  Calculated or measured creatinine clearance ≥45 mL/min&#xD;
&#xD;
               3. Other Lab Values:&#xD;
&#xD;
                    -  Amylase or lipase ≤2 X institutional ULN&#xD;
&#xD;
                    -  calcium or phosphorus, or calcium-phosphorus product &lt;55 mg2/dL2&#xD;
&#xD;
               1. Inorganic phosphorus within normal limits&#xD;
&#xD;
               2. Total corrected serum calcium within normal limits&#xD;
&#xD;
         13. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or&#xD;
             participant has had a hysterectomy.&#xD;
&#xD;
         14. For females of reproductive potential: use of highly effective contraception for at&#xD;
             least 1 month prior to screening and agreement to use such a method during study&#xD;
             participation and for an additional 3 months after the end of treatment&#xD;
             administration.&#xD;
&#xD;
         15. For males of reproductive potential: use of condoms or other methods to ensure&#xD;
             effective contraception with partner and for an additional 1 month after the end of&#xD;
             treatment administration. A condom is required to be used also by vasectomized men as&#xD;
             well as during intercourse with a male partner to prevent delivery of the drug via&#xD;
             seminal fluid.&#xD;
&#xD;
         16. Agreement to adhere to Lifestyle Considerations throughout study duration.&#xD;
&#xD;
         17. Participants who received chemotherapy must have recovered (Common Terminology&#xD;
             Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy&#xD;
             except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A&#xD;
             washout period of at least 21 days is required between last chemotherapy dose and Day&#xD;
             1 (provided the patient did not receive radiotherapy).&#xD;
&#xD;
         18. Participants who received radiotherapy must have completed and fully recovered from&#xD;
             the acute effects of radiotherapy. A washout period of at least 14 days is required&#xD;
             between end of radiotherapy and Day 1.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Have a history of liver transplant.&#xD;
&#xD;
          2. Have impairment of gastrointestinal (GI) function or GI disease that may significantly&#xD;
             alter the absorption of oral infigratinib (e.g., ulcerative diseases, uncontrolled&#xD;
             nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).&#xD;
&#xD;
          3. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at&#xD;
             time of initiating study treatment), fungal infection, or detectable viral infection&#xD;
             (such as known human immunodeficiency virus positivity or with known active hepatitis&#xD;
             B or C [for example, hepatitis B surface antigen positive]. Screening is not required&#xD;
             for enrollment.&#xD;
&#xD;
          4. Have a history and/or current evidence of extensive tissue calcification including,&#xD;
             but not limited to, the soft tissue, kidneys, intestine, myocardium, vascular system,&#xD;
             and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal&#xD;
             calcifications, and asymptomatic coronary calcification.&#xD;
&#xD;
          5. Have current evidence of corneal or retinal disorder/keratopathy including, but not&#xD;
             limited to, bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis&#xD;
             confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic conditions&#xD;
             assessed by the investigator to pose minimal risk for study participation may be&#xD;
             enrolled in the study.&#xD;
&#xD;
          6. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g.,&#xD;
             parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis&#xD;
             etc.&#xD;
&#xD;
          7. Have had a recent (≤3 months prior to first dose of study drug) transient ischemic&#xD;
             attack or stroke.&#xD;
&#xD;
          8. CTCAE (v5.0) Grade ≥2 hearing loss.&#xD;
&#xD;
          9. CTCAE (v5.0) Grade ≥2 neuropathy.&#xD;
&#xD;
         10. Have clinically significant cardiac disease including any of the following:&#xD;
&#xD;
               1. Known congestive heart failure requiring treatment (New York Heart Association&#xD;
                  Grade ≥2), LVEF &lt;50% or local lower limit of normal as determined by MUGA scan or&#xD;
                  echocardiogram (ECHO), or uncontrolled hypertension (refer to the European&#xD;
                  Society of Cardiology and European Society of Hypertension guidelines [Williams&#xD;
                  et al 2018]).&#xD;
&#xD;
               2. Presence of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade ≥2&#xD;
                  ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction&#xD;
                  abnormality.&#xD;
&#xD;
               3. Unstable angina pectoris or acute myocardial infarction ≤3 months prior to first&#xD;
                  dose of study drug.&#xD;
&#xD;
               4. QTcF &gt;470 msec (males and females). Note: If the QTcF is &gt;470 msec in the first&#xD;
                  ECG, a total of 3 ECGs separated by at least 5 minutes should be performed. If&#xD;
                  the average of these 3 consecutive results for QTcF is ≤470 msec, the participant&#xD;
                  meets eligibility in this regard.&#xD;
&#xD;
               5. Known history of congenital long QT syndrome.&#xD;
&#xD;
         11. Has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment&#xD;
             of the investigator, would preclude participation in this study (for example,&#xD;
             interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe&#xD;
             renal impairment [e.g. estimated creatinine clearance &lt;30ml/min], history of major&#xD;
             surgical resection involving the stomach or small bowel, or preexisting Crohn's&#xD;
             disease or ulcerative colitis or a preexisting chronic condition resulting in baseline&#xD;
             Grade 2 or higher diarrhea).&#xD;
&#xD;
         12. Prior therapy with any mitogen-activated protein kinase (MEK) or FGFR inhibitor. Prior&#xD;
             therapy is defined as a therapeutic dosing, as determined by the Investigator.&#xD;
&#xD;
         13. Are currently receiving or are planning to receive during participation in this study,&#xD;
             treatment with agents that are known strong inducers or inhibitors of CYP3A4 and&#xD;
             medications which increase serum phosphorus and/or calcium concentration. Participants&#xD;
             are not permitted to receive enzyme-inducing anti-epileptic drugs, including&#xD;
             carbamazepine, phenytoin, phenobarbital, and primidone.&#xD;
&#xD;
         14. Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise.&#xD;
             Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.&#xD;
&#xD;
         15. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents,&#xD;
             infigratinib, or their excipients.&#xD;
&#xD;
         16. Treatment with another investigational drug or other intervention within 30 days prior&#xD;
             to enrollment or within 5 half-lives of the investigational product, whichever is&#xD;
             longer.&#xD;
&#xD;
         17. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star&#xD;
             fruits, pomelos, Seville oranges or products containing juice of these fruits within 7&#xD;
             days prior to first dose of study drug.&#xD;
&#xD;
         18. Have used medications known to prolong the QT interval and/or are associated with a&#xD;
             risk of Torsades de Pointes (TdP) 7 days prior to first dose of study drug.&#xD;
&#xD;
         19. Have used amiodarone within 90 days prior to first dose of study drug.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Chandler Regional Medical Center</name>
      <address>
        <city>Chandler</city>
        <state>Arizona</state>
        <zip>85224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph's Hospital and Medical Center</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HonorHealth Scottsdale Osborn Medical Center</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <zip>85251</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.ivybraintumorcenter.org/</url>
    <description>Ivy Brain Tumor Center Website</description>
  </link>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 27, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>May 15, 2023</last_update_submitted>
  <last_update_submitted_qc>May 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 17, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>St. Joseph's Hospital and Medical Center, Phoenix</investigator_affiliation>
    <investigator_full_name>Nader Sanai</investigator_full_name>
    <investigator_title>Deputy Director, Ivy Brain Tumor Center</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Glioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infigratinib</mesh_term>
  </intervention_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/NCT04424966
org study id: 2020-08
secondary id: 20-500-092-34-38
nct id: NCT04424966
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This trial is an open-label, multicenter, Phase 0 trial that will enroll up to 20
      participants with recurrent high-grade glioma with FGFR1 K656E or FGFR3 K650E mutation or
      FGFR3-TACC3 translocation which are scheduled for resection. In the lead-in cohort, a total
      of 20 participants will be enrolled into the proposed phase 0 clinical trial. Participants
      will be administered infigratinib prior to surgical resection of their tumor.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase 0: Concentration of infigratinib in enhancing and non-enhancing tumor tissue
time frame: Day 7 at 8 hours post dose
description: Phase 0: Tumor tissue will be collected approximately 8hrs after infigratinib administration on Day 7 to determine the concentration of infigratinib in the tumor tissue.
measure: Phase 0: Concentration of infigratinib in plasma (0-24H)
time frame: Day 7 at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose
description: Samples will be collected at 8 timepoints during 24 hours after infigratinib administration on Day 7.
measure: Phase 0: Concentration of infigratinib in CSF
time frame: Day 7 at 8 hours post dose
description: CSF will be collected at approximately 8hrs after infigratinib administration on Day 7 to determine the concentration of infigratinib in CSF.
measure: Expansion Cohort: 6-month Progression-free survival
time frame: 6 months from the time of surgery
description: Expansion Cohort: 6-month Progression-free survival (PFS6) rate from time of surgery to date of recurrence
measure: Phase 0: PD Analysis
time frame: Intraoperatively
description: Phase 0: percentage of pERK+, MIB-1+ and Cleaved Caspase 3+ cells from the surgical tissue will be quantified and compared to baseline archival tissue.
measure: Number of Adverse Events
time frame: up to 30 days after the last study dose
description: Number of Adverse Events
measure: Incidence of drug-related toxicity
time frame: up to 30 days after the last study dose
description: Drug-related toxicity
measure: Incidence of treatment-emergent adverse events
time frame: up to 30 days after the last study dose
description: Treatment-emergent adverse events
measure: Number of Deaths
time frame: up to 60 months
description: Number and Incidence of Deaths
measure: Number of clinical laboratory abnormalities per CTCAE
time frame: up to 30 days after the last study dose
description: Clinical laboratory abnormalities per CTCAE
arm group label: Arm 1
arm group type: Experimental
description: Phase 0: 125 mg of infigratinib administered orally for 7 days prior to surgical resection.
Expansion Cohort: 125 mg of infigratinib administered orally for 21 days of a 28-day treatment cycles.
intervention type: Drug
intervention name: Infigratinib
description: The Phase 0 study will include treatment of recurrent high-grade glioma participants with 125 mg of infigratinib 7 days prior to surgical resection. Participants with tumors demonstrating PK-response will continue treatment with the same dose continuously for 21 days in 28-day cycles after surgery.
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
country: United States
url: https://www.ivybraintumorcenter.org/
description: Ivy Brain Tumor Center Website
responsible party type: Sponsor-Investigator
investigator affiliation: St. Joseph's Hospital and Medical Center, Phoenix
investigator full name: Nader Sanai
investigator title: Deputy Director, Ivy Brain Tumor Center
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Infigratinib
sharing ipd: Undecided