APG101 in Glioblastoma

Study Overview
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Brief Summary
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This is a phase II study of APG101 + reirradiation (RT) versus reirradiation. Patients suffering from a malignant brain tumor called glioblastoma having a first or second progression can be included. They will be randomized to RT or RT + APG101. APG101 is a fusion protein (similar to an antibody) and will be administered as a weekly infusion. Patients can stay in this study as long as they benefit from the participation (no fixed end). In this trial, 30-35 sites in Germany, Austria and Russia take part.

Detailed Description
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In this phase II trial, patients with a recurrence / progression of glioblastoma (first or second progression) either not being eligible for tumour resection or having macroscopic residual tumour after resection of the recurrence can be included (tumor size must 1-4 cm in T1-weighted MRI). They must be candidates for a re-irradiation and will then be randomized in a 1:2 ratio to re-irradiation alone or re-irradiation + 400mg APG101 as a weekly intravenous infusion. Radiotherapy (RT) is considered standard of care and not a study procedure. As prior therapies, a first radiotherapy (maximal dose of 60 Gy; at least 8 months since the end of preirradiation), a prior surgery (at least for histology) and at least one Temozolomide-containing chemotherapy are mandatory; patients with prior treatment with bevacizumab, iodine seeds and/or brachytherapy are not eligible. The patients' steroid dose must be stable or decreasing upon inclusion. The number of patients to be included in this study is up to 83 (depending on the statistical 2-step SIMON design). Primary objective: 6 months rate of progression free survival (PFS6). Subjects can participate in this study as long as a clinical benefit is considered by the treating physician. MRI tumour imaging will be carried out every 6 weeks.

Official Title
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A Phase II, Randomized, Open-label, Multi-centre Study of Weekly APG101 + Reirradiation Versus Reirradiation in the Treatment of Patients With First or Second Progression of Glioblastoma

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: APG101
* Procedure: Blood drawing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients with a recurrence / progression of glioblastoma either not being eligible for tumour resection or having macroscopic residual tumour after resection of the recurrence Diagnosis of glioblastoma must be proven histologically and progress must be documented by MRI. MRI images must not be older than 2 weeks before first dosing/start of RT Not more than two prior therapy regimens including one or two resections, one or two chemotherapies of which one must have been TMZ-containing and one radiotherapy (RT) for the brain tumour Previous irradiation therapy of the primary tumour with a maximal dose of 60 Gy; at least 8 months since the end of preirradiation Candidate for reirradiation with recurrent tumour visible on MRI-T1 (Gd) and with the largest diameter measuring 1 cm to 4 cm Informed consent Age at least 18 years, smoking or non-smoking, of any ethnic origin Karnofsky performance index (KPI) ≥ 60% Neutrophile counts > 1500/μl / Platelet counts > 80.000/μl / Haemoglobin > 10 g/dl / Serum creatinine < 1.5-fold upper normal range / Bilirubin, AST or ALT < 2,5-fold upper normal range unless attributed to anticonvulsants / Alkaline phosphatase < 2,5-fold upper normal range Adequate contraception Stable or decreasing treatment with steroids within 5 days before treatment start Exclusion Criteria: More than one RT of brain, prior first radiotherapy with more than 60 Gy Cumulative total dose on the optical chiasm >54 Gy for 2 Gy/fraction, α/β=2 Prior treatment with bevacizumab, iodine seeds and/or brachytherapy Unable to undergo MRI Past medical history of diseases with poor prognosis according to the judgement of the Investigator, e.g. severe coronary heart disease, severe diabetes, immune deficiency, residual deficits after stroke, severe mental retardation HIV or hepatitis infection Pregnancy or breast feeding Treatment within any other clinical trial parallel to the treatment phase of the current study or within 30 days before inclusion Known active coronary artery disease, significant cardiac arrhythmias or severe congestive heart failure (NYHA class III - IV)

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Re-Irradiation<br>33% of the patients will be randomized to reirradiation (RT) alone. They will receive 36 Gy (2 Gy per fraction) | Procedure: Blood drawing<br>* Blood drawings, e.g. for safety labs, abdominal ultrasound, ECG. Re-Irradiation is not considered a study procedure, but standard of care (inclusion criterion)<br>|
| Experimental: Re-Irradiation + APG101<br>66% of the patients will be randomized to reirradiation (RT) + 400 mg APG101 weekly. They will receive 36 Gy (2 Gy per fraction) and 400 mg APG101 weekly as an intravenous infusion | Drug: APG101<br>* 400mg weekly as intravenous infusion<br>* Other names: Recombinant fusion protein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 months rate of progression free survival (PFS6) |  | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of APG101 |  | ongoing during study | 
| Progression-free survival |  | until progression of underlying disease | 
| Objective response rates (OR) |  | ongoing during study | 
| Duration of response (DR) in responders |  | ongoing during study | 
| Overall survival |  | until study and after end of study (by 8-weekly phone calls) | 
| Quality of life |  | ongoing during study | 
| Cognitive function |  | ongoing during study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma Multiforme