ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects With Glioblastoma Multiforme

Study Overview
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Brief Summary
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Assess safety and tolerability of ADI-PEG 20 in combination with radiotherapy and Temozolomide in newly diagnosed GBM

Official Title
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Phase 1B Trial of ADI-PEG 20 Plus Radiotherapy and Temozolomide in Subjects With Newly Diagnosed Glioblastoma Multiforme

Conditions
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Glioblastoma Multiforme (GBM)

Intervention / Treatment
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* Drug: ADI-PEG20
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed, histologically confirmed GBM WHO Grade IV (any wildtype or mutant or gene type, except gliosarcoma), non-resectable or partially resected or resected. Age 20 - 75 years. Karnofsky Performance Status (KPS) ≥ 60. Expected life expectancy ≥16 weeks. Stable or decreasing corticosteroids (5 mg/day dexamethasone or equivalent) within 5 days before the first dose of ADI-PEG 20. No prior systemic therapy, immunotherapy, investigational agent, or radiation therapy. Recovered from any prior surgery and no major surgery within 2 weeks of initiating treatment (other than GBM surgery). Surgery for placement of vascular access devices is acceptable. Female subjects and male subjects must be asked to use appropriate contraception for both the male and female for the duration of the study. Male partners of female subjects and female partners of male subjects must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study if they are of childbearing potential. Females of childbearing potential must not be pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. If positive HCG pregnancy test, further evaluation to rule out pregnancy must be performed according to GCP before this subject is deemed eligible. Females not of childbearing potential must be post-menopausal (defined as cessation of regular menstrual period for at least 12 months). Informed consent must be obtained prior to study initiation. No concurrent investigational studies are allowed. Absolute neutrophil count (ANC) ≥ 1500/μL. Platelets ≥ 100,000/μL. Serum uric acid ≤ 8 mg/dL (with or without medication control). Creatinine clearance must be ≥ 40 mL/min/1.73 m2 (calculated using the Cockcroft-Gault equation: calculated creatinine clearance = (140-age (yrs)) × body weight (kg) (×0.85 if female) / 72 × serum creatinine (mg/dl). Total bilirubin ≤ 2 x upper limit of normal. ALT and AST ≤ 3 x upper limit of normal, unless liver metastases present then ≤ 5 x upper limit normal. Exclusion Criteria: Serious infection requiring treatment with systemically administered antibiotics at the time of study entrance, or an infection requiring systemic antibiotic therapy within 7 days prior to the first dose of study treatment. Pregnancy or lactation. Expected non-compliance. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), cardiac arrhythmia, or psychiatric illness, social . Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present or in the opinion of the investigator will not affect patient outcome. Subjects who had been treated with ADI-PEG 20 previously. History of uncontrolled seizure disorder not related to underlying cancer. Known HIV positivity, or active hepatitis B infection, or active hepatitis C infection (testing not required). Allergy to pegylated compounds. Allergy to E. coli drug products (such as GMCSF). Allergy to TMZ or any of its components. History of hypersensitivity to dacarbazine. Placement of Gliadel wafer at surgery. Having a co-existing condition requiring systemic treatment with either corticosteroids or immunosuppressive medication.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADI-PEG 20 plus Radiotherapy and Temozolomide<br>ADI-PEG 20 Dose: 18 and 36 mg/m2 given weekly Route of Administration: Intramuscular (IM) Radiotherapy Dose: 60 Gy in 30 daily (Monday-Friday) fractions of 2 Gy each; to start within 5 weeks of surgery (diagnostic and/or resection) Temozolomide Dose: 75 mg/m2 daily during radiotherapy; 150-200 mg/m2 for 5 days every 4 weeks (1 cycle) x 6 cycles during maintenance period Route of Administration: oral or intravenous | Drug: ADI-PEG20<br>* Investigational Medicine<br>Drug: Temozolomide<br>* Radiotherapy and TMZ are standard front-line therapy for newly diagnosed GBM.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability of ADI-PEG 20 in combination with radiotherapy and TMZ |  | Through study completion, 2.5 year anticipated | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine recommended phase 2 dose (RP2D) | RP2D will be determined by 3+3 method, depending on the Dose-Limiting Toxicity (DLT). | Through study completion, 2.5 year anticipated | 
| Measure progression free survival at the RP2D | Progression free survival was defined as the period of time from randomization to date of tumor progression or death. Tumor measurements must be noted and tumor response status by investigator should be calculated. | Baseline brain MRI is after glioma surgery (if applicable) and prior to subject receiving the first ADI-PEG 20 administration. Scans are to be performed after 1, 3 and 6 months following completion of radiation therapy. | 
| Measure overall survival at the RP2D | Overall Survival was defined as the period of time from randomization to date of death due to any cause. | Through study completion, 2.5 year anticipated | 
| Minimum blood plasma concentration [Cmin ] of ADI-PEG 20 | A pharmacokinetics measure of minimum ADI-PEG 20 concentration before the next ADI-PED 20 administration | Blood samples to be collected bi-weekly for 11 weeks, then once every 4 weeks until week36. Sample will be collected prior to ADI-PEG 20 administration | 
| Blood plasma level of arginine and citrulline | Pharmacodynamics of ADI-PEG 20 in combination with radiotherapy and TMZ | Blood samples to be collected bi-weekly for 11 weeks, then once every 4 weeks until week36. Sample will be collected prior to ADI-PEG 20 administration | 
| Plasma levels of antibodies against ADI-PEG 20 | Measurement of serum antibodies to ADI-PEG 20 to determine immunogenicity of ADI-PEG 20 in combination with radiotherapy and TMZ | Through study completion, 2.5 year anticipated | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arginine, argininosuccinate synthetase, arginine deiminase