<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/NCT03234595</url>
  </required_header>
  <id_info>
    <org_study_id>EFBPOLZ20141120</org_study_id>
    <nct_id>NCT03234595</nct_id>
  </id_info>
  <brief_title>A Phase I/IIa Study of Cerebraca Wafer Plus Adjuvant Temozolomide (TMZ) in Patients With Recurrent High Grade Glioma</brief_title>
  <official_title>Everfront Biotech Co., Ltd.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Everfront Biotech Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Everfront Biotech Co., Ltd.</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>
      A Phase I/IIa Study to Determine the Maximum Tolerated Dose (MTD) and to Evaluate the Safety&#xD;
      and Efficacy Profile of Cerebraca Wafer Plus Adjuvant Temozolomide (TMZ) in Patients With&#xD;
      Recurrent High Grade Glioma.&#xD;
&#xD;
      High grade gliomas, glioblastoma multiforme (grade IV) and anaplastic anaplastic astrocytoma&#xD;
      (Grade III), are the most comment malignant brain tumor. The cause of gliomas remains&#xD;
      unknown. Despite of several researches on environmental hazards and genetic alterations, no&#xD;
      direct causes were found.&#xD;
&#xD;
      Patient suffering from glioma usually develops symptoms such as headaches, seizures, memory&#xD;
      loss and changes in behavior in its early phase. At later stages, patients may encounter loss&#xD;
      of movement and sensation, language dysfunction and cognitive impairments depending on&#xD;
      location and size of the tumor. The average survival of glioblastoma patients is 15 months&#xD;
      regardless of the use of multimodal therapy.&#xD;
&#xD;
      (Z)-BP/polymer wafer, designated as Cerebraca wafer, is a biodegradable wafer for&#xD;
      interstitial implantation comprises (Z)-n-butylidenephthalide ((Z)-BP; the active moiety) and&#xD;
      Carboxyphenoxypropane-Sebacic Acid Copolymer (CPPSA; the excipient).&#xD;
&#xD;
      Cerebraca wafer, the first human-use drug product, is a biodegradable implant comprises&#xD;
      (Z)-n-butylidenephthalide ((Z)-BP) and CPPSA. According to pre-clinical study, (Z)-BP could&#xD;
      reduce glioma migration and invasion, it also could reduce the tumor stem cell marker gens.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There are a main study period and extended period in this study. Main study period Screening&#xD;
      Day -30~-1&#xD;
&#xD;
        1. informed consent signed/given&#xD;
&#xD;
        2. Screening evaluation Day 0~7&#xD;
&#xD;
      (1) Tumor resection and Cerebraca wafer implantation (2)Blood sampling for PK (3) Blood&#xD;
      sampling for PD (4) Evaluation Day10~24&#xD;
&#xD;
        1. Blood sampling for PK&#xD;
&#xD;
        2. Blood sampling for PD&#xD;
&#xD;
        3. Evaluation Extended period/Follow-up:Every 56 days (8 weeks) The main study will end at&#xD;
           24 weeks after all patients (including Phase I and IIa) receive Cerebraca implantation.&#xD;
           If confirmation tumor response assessment is needed, additional 4 weeks study duration&#xD;
           for Main Study Period is allowed.&#xD;
&#xD;
      All patients will be followed in the Extended Period for the efficacy and safety profiles&#xD;
      until any one of study cut-off criteria is met.&#xD;
&#xD;
      Study cut-off criteria: (Applies to phase I and IIa) (1)90% patient died or loss of follow-up&#xD;
      (2)2 years after the last patient receives Cerebraca wafer implantation&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Actual">April 30, 2023</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Determination of the DLT/MTD of Cerebraca Wafer with TMZ (Temozolomide) in patients with recurrent high grade glioma.</measure>
    <time_frame>1 year</time_frame>
    <description>It is a phase I/IIa study of Cerebraca Wafer, intracerebral implantation after resection of tumor, plus adjuvant Temozolomide (TMZ) in patients with recurrent high grade glioma (Grade III and Grade IV; anaplastic astrocytoma and glioblastoma multiforme).&#xD;
Phase I: at least 2 patients and up to 24 patients. Phase IIa: 12 patients. The main study will end at 24 weeks after all patients receive Cerebraca Wafer implantation. If confirmation tumor response assessment is needed, additional 4 weeks study duration for Main Study Period is allowed. The clinical data at Main Study Period will be summarized in a Main Study Clinical Study Report (CSR).&#xD;
All patients will be followed in the Extended Period for the efficacy and safety profiles until any one of study cut-off criteria is met, and a CSR will summarize the clinical data covering the overall study period.&#xD;
NCI-CTCAE 4.03 will be used for grading of the toxicity of Cerebraca wafer.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of the efficacy/safety profile of Cerebraca Wafer with TMZ (Temozolomide) in patients with recurrent high grade glioma.</measure>
    <time_frame>2 year</time_frame>
    <description>NCI-CTCAE 4.03 will be used for grading of the toxicity (AE) of Cerebraca wafer.&#xD;
Tumor response evaluation will be based on Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group (RANO).</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Recurrent High Grade Glioma</condition>
  <arm_group>
    <arm_group_label>single arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>There is 1 treatment arm with 4 dose cohorts in Phase I and 1 treatment arm in Phase IIa.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cerebraca wafer</intervention_name>
    <description>Eligible patients will receive Cerebraca wafer implantation with adjuvant temozolomide (TMZ) for the safety and efficacy in this study. At Phase I, the MTD will be determined by DLT. At Phase IIa, up to 12 evaluable patients will be enrolled for the efficacy and safety of Cerebraca wafer implantation. At Phase IIa, the cavity surface after tumor removal will be maximally covered by Cerebraca wafer without exceeding the MTD defined at Phase I. Patients in Phase I receive treatment as designed for Phase IIa, the data will be incorporated into Phase IIa to reduce the patient number. The overall patient number in this study is therefore between 2 to 36 evaluable patients.</description>
    <arm_group_label>single arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Female or male, age ≥ 20 years old&#xD;
&#xD;
          2. Patient has diagnosed recurrent high grade glioma, including anaplastic astrocytoma&#xD;
             and glioblastoma multiforme&#xD;
&#xD;
          3. Patients have enough cavity after glioma resection for planned number of wafer&#xD;
             implantation (by Investigator's judgment)&#xD;
&#xD;
          4. Patients have unilateral single focus of tumor in cerebrum&#xD;
&#xD;
          5. Patients have the 1st time recurrence of glioma&#xD;
&#xD;
          6. Patients undergone standard therapy for their prior glioma episode; for patients with&#xD;
             anaplastic astrocytoma, the prior standard therapy should include surgical resection,&#xD;
             radiation and adjuvant temozolomide (or PCV [procarzine, lomustine and vincristine];&#xD;
             for patients with glioblastoma multiforme the prior standard therapy should include&#xD;
             surgical resection, radiation and adjuvant temozolomide&#xD;
&#xD;
          7. Patients with Karnofsky Performance Score (KPS) ≥ 50&#xD;
&#xD;
          8. Patients are recovered from toxicities from prior systemic therapies and have adequate&#xD;
             hematopoietic function at screening and before using study medication&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1,000 cells /mm3&#xD;
&#xD;
               -  Platelets ≥ 100,000 /mm3&#xD;
&#xD;
               -  Total white blood cell (WBC) ≥ 2,500 cells /mm3&#xD;
&#xD;
               -  Total bilirubin ≤ 2.5 mg/dL&#xD;
&#xD;
               -  AST ≤ 4 x ULN&#xD;
&#xD;
               -  ALT ≤ 4 x ULN&#xD;
&#xD;
               -  ALP ≤ 5 x ULN&#xD;
&#xD;
               -  Creatinine ≤ 2.0 mg/dL&#xD;
&#xD;
               -  GFR ≥ 30 ml/min/1.73m2&#xD;
&#xD;
          9. Patient with no or mild organ impairment&#xD;
&#xD;
         10. Patients who are eligible and able to participate in the study and accept to enter the&#xD;
             study by signing written informed consent forms&#xD;
&#xD;
         11. Patients agrees not to use food supplementary or dietary that contains Angelica&#xD;
             sinensis after Screening Visit to Day 21&#xD;
&#xD;
         12. All male patients and female patients with child-bearing potential (between puberty&#xD;
             and 2 years after menopause) should use appropriate contraception method(s) for at&#xD;
             least 4 weeks after Cerebraca wafer treatment and TMZ treatment (whichever is longer)&#xD;
             shown below.&#xD;
&#xD;
               -  Total abstinence (when this is in line with the preferred and usual lifestyle of&#xD;
                  the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,&#xD;
                  post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
                  contraception).&#xD;
&#xD;
               -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.&#xD;
                  In case of oophorectomy alone, only when the reproductive status of the woman has&#xD;
                  been confirmed by follow up hormone level assessment.&#xD;
&#xD;
               -  Male sterilization (at least 6 months prior to screening). For female subjects on&#xD;
                  the study, the vasectomized male partner should be the sole partner for that&#xD;
                  subject&#xD;
&#xD;
               -  Combination of any two of the following (a+b or a+c, or b+c):&#xD;
&#xD;
                    1. Use of oral, injected or implanted hormonal methods of contraception or&#xD;
                       other forms of hormonal contraception that have comparable efficacy (failure&#xD;
                       rate &lt;1%), for example hormone vaginal ring or transdermal hormone&#xD;
                       contraception.&#xD;
&#xD;
                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).&#xD;
&#xD;
                    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or&#xD;
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal&#xD;
                       suppository.&#xD;
&#xD;
        Phase IIa The inclusion criteria for Phase IIa is the same as in Phase I&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Phase I and IIa&#xD;
&#xD;
          1. Patient who has participated in other investigational studies within 4 weeks prior to&#xD;
             receive Cerebraca wafer&#xD;
&#xD;
          2. Patient with known or suspected hypersensitivity to Cerebraca wafer, TMZ or the&#xD;
             excipient&#xD;
&#xD;
          3. Patient has tumor that cannot be surgically removed without significantly affecting&#xD;
             vital function&#xD;
&#xD;
          4. Patient's glioma locates in the area that is not suitable for Cerebraca wafer&#xD;
             implantation&#xD;
&#xD;
          5. Patient has external-beam radiation therapy within 4 weeks before study entry&#xD;
&#xD;
          6. Patient has other severe and/or life-threatening disease(s) with life expectancy less&#xD;
             than 12 months&#xD;
&#xD;
          7. Patient has immuno-compromised condition, or is with known autoimmune conditions or is&#xD;
             human immunodeficiency virus (HIV) seropositive.&#xD;
&#xD;
          8. Patient with medical, social or psychological factors interfering with compliance of&#xD;
             the study&#xD;
&#xD;
          9. Patient has on-going moderate to severe organ impairment other than study indication&#xD;
             that may confound the efficacy evaluation, safety evaluation or usage of TMZ&#xD;
&#xD;
         10. At Phase I, patient is planning to use strong cytochrome P450 modulator.&#xD;
&#xD;
         11. Female patients are lactating, pregnant, or planned to be pregnant&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hualien Tzu Chi Hospital</name>
      <address>
        <city>Hualien City</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Taichung Veterans General Hospital</name>
      <address>
        <city>Taichung</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tri-Service General Hospital</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>June 28, 2023</last_update_submitted>
  <last_update_submitted_qc>June 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cerebraca wafer</keyword>
  <keyword>Recurrent high grade glioma</keyword>
  <keyword>anaplastic astrocytoma</keyword>
  <keyword>glioblastoma multiforme</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_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/NCT03234595
org study id: EFBPOLZ20141120
nct id: NCT03234595
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
A Phase I/IIa Study to Determine the Maximum Tolerated Dose (MTD) and to Evaluate the Safety
      and Efficacy Profile of Cerebraca Wafer Plus Adjuvant Temozolomide (TMZ) in Patients With
      Recurrent High Grade Glioma.

      High grade gliomas, glioblastoma multiforme (grade IV) and anaplastic anaplastic astrocytoma
      (Grade III), are the most comment malignant brain tumor. The cause of gliomas remains
      unknown. Despite of several researches on environmental hazards and genetic alterations, no
      direct causes were found.

      Patient suffering from glioma usually develops symptoms such as headaches, seizures, memory
      loss and changes in behavior in its early phase. At later stages, patients may encounter loss
      of movement and sensation, language dysfunction and cognitive impairments depending on
      location and size of the tumor. The average survival of glioblastoma patients is 15 months
      regardless of the use of multimodal therapy.

      (Z)-BP/polymer wafer, designated as Cerebraca wafer, is a biodegradable wafer for
      interstitial implantation comprises (Z)-n-butylidenephthalide ((Z)-BP; the active moiety) and
      Carboxyphenoxypropane-Sebacic Acid Copolymer (CPPSA; the excipient).

      Cerebraca wafer, the first human-use drug product, is a biodegradable implant comprises
      (Z)-n-butylidenephthalide ((Z)-BP) and CPPSA. According to pre-clinical study, (Z)-BP could
      reduce glioma migration and invasion, it also could reduce the tumor stem cell marker gens.
There are a main study period and extended period in this study. Main study period Screening
      Day -30~-1

        1. informed consent signed/given

        2. Screening evaluation Day 0~7

      (1) Tumor resection and Cerebraca wafer implantation (2)Blood sampling for PK (3) Blood
      sampling for PD (4) Evaluation Day10~24

        1. Blood sampling for PK

        2. Blood sampling for PD

        3. Evaluation Extended period/Follow-up:Every 56 days (8 weeks) The main study will end at
           24 weeks after all patients (including Phase I and IIa) receive Cerebraca implantation.
           If confirmation tumor response assessment is needed, additional 4 weeks study duration
           for Main Study Period is allowed.

      All patients will be followed in the Extended Period for the efficacy and safety profiles
      until any one of study cut-off criteria is met.

      Study cut-off criteria: (Applies to phase I and IIa) (1)90% patient died or loss of follow-up
      (2)2 years after the last patient receives Cerebraca wafer implantation
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Determination of the DLT/MTD of Cerebraca Wafer with TMZ (Temozolomide) in patients with recurrent high grade glioma.
time frame: 1 year
description: It is a phase I/IIa study of Cerebraca Wafer, intracerebral implantation after resection of tumor, plus adjuvant Temozolomide (TMZ) in patients with recurrent high grade glioma (Grade III and Grade IV; anaplastic astrocytoma and glioblastoma multiforme).
Phase I: at least 2 patients and up to 24 patients. Phase IIa: 12 patients. The main study will end at 24 weeks after all patients receive Cerebraca Wafer implantation. If confirmation tumor response assessment is needed, additional 4 weeks study duration for Main Study Period is allowed. The clinical data at Main Study Period will be summarized in a Main Study Clinical Study Report (CSR).
All patients will be followed in the Extended Period for the efficacy and safety profiles until any one of study cut-off criteria is met, and a CSR will summarize the clinical data covering the overall study period.
NCI-CTCAE 4.03 will be used for grading of the toxicity of Cerebraca wafer.
measure: Evaluation of the efficacy/safety profile of Cerebraca Wafer with TMZ (Temozolomide) in patients with recurrent high grade glioma.
time frame: 2 year
description: NCI-CTCAE 4.03 will be used for grading of the toxicity (AE) of Cerebraca wafer.
Tumor response evaluation will be based on Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group (RANO).
arm group label: single arm
arm group type: Experimental
description: There is 1 treatment arm with 4 dose cohorts in Phase I and 1 treatment arm in Phase IIa.
intervention type: Drug
intervention name: Cerebraca wafer
description: Eligible patients will receive Cerebraca wafer implantation with adjuvant temozolomide (TMZ) for the safety and efficacy in this study. At Phase I, the MTD will be determined by DLT. At Phase IIa, up to 12 evaluable patients will be enrolled for the efficacy and safety of Cerebraca wafer implantation. At Phase IIa, the cavity surface after tumor removal will be maximally covered by Cerebraca wafer without exceeding the MTD defined at Phase I. Patients in Phase I receive treatment as designed for Phase IIa, the data will be incorporated into Phase IIa to reduce the patient number. The overall patient number in this study is therefore between 2 to 36 evaluable patients.
arm group label: single arm
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
country: Taiwan
responsible party type: Sponsor
mesh term: Glioma
mesh term: Recurrence