A Phase I/IIa Study of Cerebraca Wafer Plus Adjuvant Temozolomide (TMZ) in Patients With Recurrent High Grade Glioma

Study Overview
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Brief Summary
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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.

Detailed Description
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There are a main study period and extended period in this study. Main study period Screening Day -30 -1 informed consent signed/given 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 Blood sampling for PK Blood sampling for PD 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

Official Title
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Everfront Biotech Co., Ltd.

Conditions
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Recurrent High Grade Glioma

Intervention / Treatment
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* Drug: Cerebraca wafer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male, age ≥ 20 years old Patient has diagnosed recurrent high grade glioma, including anaplastic astrocytoma and glioblastoma multiforme Patients have enough cavity after glioma resection for planned number of wafer implantation (by Investigator's judgment) Patients have unilateral single focus of tumor in cerebrum Patients have the 1st time recurrence of glioma Patients undergone standard therapy for their prior glioma episode; for patients with anaplastic astrocytoma, the prior standard therapy should include surgical resection, radiation and adjuvant temozolomide (or PCV [procarzine, lomustine and vincristine]; for patients with glioblastoma multiforme the prior standard therapy should include surgical resection, radiation and adjuvant temozolomide Patients with Karnofsky Performance Score (KPS) ≥ 50 Patients are recovered from toxicities from prior systemic therapies and have adequate hematopoietic function at screening and before using study medication Absolute neutrophil count (ANC) ≥ 1,000 cells /mm3 Platelets ≥ 100,000 /mm3 Total white blood cell (WBC) ≥ 2,500 cells /mm3 Total bilirubin ≤ 2.5 mg/dL AST ≤ 4 x ULN ALT ≤ 4 x ULN ALP ≤ 5 x ULN Creatinine ≤ 2.0 mg/dL GFR ≥ 30 ml/min/1.73m2 Patient with no or mild organ impairment Patients who are eligible and able to participate in the study and accept to enter the study by signing written informed consent forms Patients agrees not to use food supplementary or dietary that contains Angelica sinensis after Screening Visit to Day 21 All male patients and female patients with child-bearing potential (between puberty and 2 years after menopause) should use appropriate contraception method(s) for at least 4 weeks after Cerebraca wafer treatment and TMZ treatment (whichever is longer) shown below. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception). Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject Combination of any two of the following (a+b or a+c, or b+c): Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. Phase IIa The inclusion criteria for Phase IIa is the same as in Phase I Exclusion Criteria: Phase I and IIa Patient who has participated in other investigational studies within 4 weeks prior to receive Cerebraca wafer Patient with known or suspected hypersensitivity to Cerebraca wafer, TMZ or the excipient Patient has tumor that cannot be surgically removed without significantly affecting vital function Patient's glioma locates in the area that is not suitable for Cerebraca wafer implantation Patient has external-beam radiation therapy within 4 weeks before study entry Patient has other severe and/or life-threatening disease(s) with life expectancy less than 12 months Patient has immuno-compromised condition, or is with known autoimmune conditions or is human immunodeficiency virus (HIV) seropositive. Patient with medical, social or psychological factors interfering with compliance of the study Patient has on-going moderate to severe organ impairment other than study indication that may confound the efficacy evaluation, safety evaluation or usage of TMZ At Phase I, patient is planning to use strong cytochrome P450 modulator. Female patients are lactating, pregnant, or planned to be pregnant

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: single arm<br>There is 1 treatment arm with 4 dose cohorts in Phase I and 1 treatment arm in Phase IIa. | Drug: Cerebraca wafer<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the DLT/MTD of Cerebraca Wafer with TMZ (Temozolomide) in patients with recurrent high grade glioma. | 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. | 1 year | 
| Evaluation of the efficacy/safety profile of Cerebraca Wafer with TMZ (Temozolomide) in patients with recurrent high grade glioma. | 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). | 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebraca wafer, Recurrent high grade glioma, anaplastic astrocytoma, glioblastoma multiforme