Phase IIb Clinical Trial With TGF-β2 Antisense Compound AP 12009 for Recurrent or Refractory High-grade Glioma

Study Overview
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Brief Summary
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In this multinational dose finding Phase IIb study the efficacy and safety of two doses of AP 12009 compared to standard chemotherapy (temozolomide or PCV) is investigated in adult patients with confirmed recurrent high-grade glioma.

Detailed Description
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The purpose of this study is to compare the safety and efficacy of two doses of AP 12009 and standard chemotherapy in adult patients with recurrent high-grade glioma (anaplastic astrocytoma [AA], WHO grade III; or glioblastoma [GBM], WHO grade IV). AP 12009 is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human transforming growth factor-beta2 (TGF-beta2). The growth factor TGF-beta plays a key role in malignant progression of various tumors by inducing proliferation, invasion, metastasis, angiogenesis and escape from immunosurveillance. It has been shown that in a number of tumor types the degree of TGF-beta production strongly correlates with tumor grade and stage. In patients with high-grade glioma, the TGF-beta2 overexpression is associated with disease stage, clinical prognosis and the immunodeficient state of the patients.

Official Title
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Multi-national, Open-label, Active-controlled, Randomized Dose-finding Study to Evaluate Efficacy of 2 Doses of AP 12009 in Recurrent Glioma, Administered Intratumorally as Continuous High-flow Microperfusion Over 7 Days Every Other Week

Conditions
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Glioblastoma, Anaplastic Astrocytoma

Intervention / Treatment
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* Drug: AP 12009 10 µM
* Drug: AP 12009 80 µM
* Drug: temozolomide or PCV
* Device: Drug delivery system for administration of AP 12009
* Procedure: Placement of Drug Delivery System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed diagnosis of recurrent or refractory high-grade glioma (anaplastic astrocytoma, WHO grade III; or glioblastoma, WHO grade IV) Supratentorial localization No more than two chemotherapy regimens including radiochemotherapy since primary diagnosis Eligible for either TMZ or PCV treatment Recovery from acute toxicity caused by any previous therapy Adequate organ functions KPS at least 70% Exclusion Criteria: Tumor surgery within 2 weeks prior to study entry Radiation therapy within 8 weeks prior to study entry Chemotherapy within 4 weeks prior to study entry (nitrosureas: 6 weeks) No more than 3 mg/day dexamethasone (or equivalent) at baseline Prior TGF-beta targeted therapy or tumor vaccination Baseline MRI shows mass effect Known active infection with HIV, HBV, or HCV; acute viral, bacterial, or fungal infection Significant psychiatric disorders/legal incapacity or a limited legal capacity

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AP 12009 10 µM<br> | Drug: AP 12009 10 µM<br>* 10 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks<br>Device: Drug delivery system for administration of AP 12009<br>* Drug delivery system for Convection Enhanced Delivery consists of a portable pump with drug reservoir and infusion line. Main implanted parts are the port access system and the intratumoral catheter.<br>Procedure: Placement of Drug Delivery System<br>* Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.<br>|
| Experimental: AP 12009 80 µM<br> | Drug: AP 12009 80 µM<br>* 80 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks<br>Device: Drug delivery system for administration of AP 12009<br>* Drug delivery system for Convection Enhanced Delivery consists of a portable pump with drug reservoir and infusion line. Main implanted parts are the port access system and the intratumoral catheter.<br>Procedure: Placement of Drug Delivery System<br>* Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.<br>|
| Active Comparator: Chemotherapy<br> | Drug: temozolomide or PCV<br>* temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle; PCV (procarbazine, CCNU, vincristine): standard regimen<br>* Other names: CeeNU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate of two AP 12009 dose groups and control group assessed by the evaluation of tumor size on brain MRI scans |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | overall | 
| Overall survival |  | six- and twelve-month | 
| Response rates |  | at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable) | 
| Progression-free survival |  | six-month | 
| Time to progression |  |  | 
| Time to response |  |  | 
| Best of all response rates assessed by survival status and variation of tumor size on brain MRI |  |  | 
| Change of quality of life and Karnofsky Performance Status (KPS) |  | at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable) | 
| Best of all response rates |  |  | 
| Safety and tolerability |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Anaplastic astrocytoma, Antisense, Cancer, Transforming growth factor beta2 (TGF-beta2), Targeted therapy, Immunotherapy, Brain tumor, Central nervous system (CNS), Convection-enhanced delivery (CED) / microperfusion, Locoregional application