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

Primary Purpose

Glioblastoma, Anaplastic Astrocytoma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
AP 12009 10 µM
AP 12009 80 µM
temozolomide or PCV
Drug delivery system for administration of AP 12009
Placement of Drug Delivery System
Sponsored by
Isarna Therapeutics GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring 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

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Universitätsklinik Innsbruck; Abteilung für Neurochirurgie
  • Landes-Nervenklinik Wagner-Jauregg
  • Kaiser Franz Josef Spital, Abteilung für Neurologie
  • Sarajishvili Institute of Clinical Neurology and Neurosurgery
  • Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte
  • Klinik und Poliklinik für Neurologie
  • Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
  • Universitätsklinikum Gießen, Neurochirurgische Universitätsklinik
  • Universitätsklinikum Kiel, Klinik für Neurochirurgie
  • Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie
  • Universitätsklinik Magdeburg, Klinik für Neurochirurgie
  • Universitätskliniken Mainz, Neurochirurgische Klinik und Poliklinik
  • Universitätsklinikum Münster, Klinik und Poliklinik für Neurochirurgie
  • Klinikum und Poliklinik für Neurologie, Universität Regensburg
  • Klinikum Saarbrücken, Neurochirurgie
  • Neurologische Universitätsklinik Tübingen
  • Department of Neurosurgery, Amrita Institute of Medical Sciences & Research Centre
  • Sree Chitra Tirunal Institute for Medical Sciences & Technology, Department of Neurosurgery
  • Manipal Hospital; Manipal Institute for Neurological Disorders
  • Department of Neurosurgery, National Institute of Mental Health and Neurosciences
  • Department of Medical Oncology, Nizam's Institute of Medical Sciences
  • Department of Neurosurgery, LTMG Hospital & LTM Medical College
  • Department of Neurosurgery, Neurosciences Center
  • Department of Neurological Sciences, Christian Medical College & Hospital
  • Soroka Medical Center, Neurosurgery Department
  • Rambam Medical Center, Neurosurgery Department
  • Rabin Medical Center, Neurosurgery Department
  • Sverdlovsk Regional Oncological Clinic
  • Republican Clinical Hospital of Ministry of Health of Tatarstan Republic
  • Burdenko Neurosurgery Research Institute
  • Omsk State Medical Academy; State Educational Institution of Higher Professional Education
  • State Institution of Healthcare, Samara Regional Clinical Hospital in the name of M.I. Kalinin
  • Polenov Neurosurgery Research Institute
  • Military Medical Academy named after I.S.M. Kirov, Neurosurgery Department
  • Medical Center "XXI century"
  • Tcheliabinsk Regional Clinical Hospital; State Medical Institution for Prophylaxis and Treatment

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

AP 12009 10 µM

AP 12009 80 µM

Chemotherapy

Arm Description

Outcomes

Primary Outcome Measures

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

Overall survival
Overall survival
Response rates
Progression-free survival
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)
Best of all response rates
Safety and tolerability

Full Information

First Posted
February 5, 2007
Last Updated
December 2, 2013
Sponsor
Isarna Therapeutics GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT00431561
Brief Title
Phase IIb Clinical Trial With TGF-β2 Antisense Compound AP 12009 for Recurrent or Refractory High-grade Glioma
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2013
Overall Recruitment Status
Completed
Study Start Date
April 2003 (undefined)
Primary Completion Date
March 2009 (Actual)
Study Completion Date
March 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Isarna Therapeutics GmbH

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Anaplastic Astrocytoma
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
141 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AP 12009 10 µM
Arm Type
Experimental
Arm Title
AP 12009 80 µM
Arm Type
Experimental
Arm Title
Chemotherapy
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
AP 12009 10 µM
Intervention Description
10 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Intervention Type
Drug
Intervention Name(s)
AP 12009 80 µM
Intervention Description
80 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Intervention Type
Drug
Intervention Name(s)
temozolomide or PCV
Other Intervention Name(s)
Temodar, Temodal, TMZ, lomustine, Cecenu, CeeNU
Intervention Description
temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle; PCV (procarbazine, CCNU, vincristine): standard regimen
Intervention Type
Device
Intervention Name(s)
Drug delivery system for administration of AP 12009
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Placement of Drug Delivery System
Intervention Description
Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
Overall survival
Time Frame
overall
Title
Overall survival
Time Frame
six- and twelve-month
Title
Response rates
Time Frame
at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable)
Title
Progression-free survival
Time Frame
six-month
Title
Time to progression
Title
Time to response
Title
Best of all response rates assessed by survival status and variation of tumor size on brain MRI
Title
Change of quality of life and Karnofsky Performance Status (KPS)
Time Frame
at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable)
Title
Best of all response rates
Title
Safety and tolerability

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ulrich Bogdahn, MD
Organizational Affiliation
University of Regensburg, Dept. of Neurology, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitätsklinik Innsbruck; Abteilung für Neurochirurgie
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria
Facility Name
Landes-Nervenklinik Wagner-Jauregg
City
Linz
ZIP/Postal Code
4020
Country
Austria
Facility Name
Kaiser Franz Josef Spital, Abteilung für Neurologie
City
Wien
ZIP/Postal Code
1100
Country
Austria
Facility Name
Sarajishvili Institute of Clinical Neurology and Neurosurgery
City
Tbilisi
ZIP/Postal Code
0114
Country
Georgia
Facility Name
Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Klinik und Poliklinik für Neurologie
City
Cottbus
ZIP/Postal Code
03048
Country
Germany
Facility Name
Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Universitätsklinikum Gießen, Neurochirurgische Universitätsklinik
City
Gießen
ZIP/Postal Code
35392
Country
Germany
Facility Name
Universitätsklinikum Kiel, Klinik für Neurochirurgie
City
Kiel
ZIP/Postal Code
24106
Country
Germany
Facility Name
Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitätsklinik Magdeburg, Klinik für Neurochirurgie
City
Magdeburg
ZIP/Postal Code
39120
Country
Germany
Facility Name
Universitätskliniken Mainz, Neurochirurgische Klinik und Poliklinik
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Universitätsklinikum Münster, Klinik und Poliklinik für Neurochirurgie
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Klinikum und Poliklinik für Neurologie, Universität Regensburg
City
Regensburg
ZIP/Postal Code
93053
Country
Germany
Facility Name
Klinikum Saarbrücken, Neurochirurgie
City
Saarbrücken
ZIP/Postal Code
66119
Country
Germany
Facility Name
Neurologische Universitätsklinik Tübingen
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Department of Neurosurgery, Amrita Institute of Medical Sciences & Research Centre
City
Cochin
State/Province
Kerala
ZIP/Postal Code
682026
Country
India
Facility Name
Sree Chitra Tirunal Institute for Medical Sciences & Technology, Department of Neurosurgery
City
Trivandrum
State/Province
Kerala
ZIP/Postal Code
695011
Country
India
Facility Name
Manipal Hospital; Manipal Institute for Neurological Disorders
City
Bangalore
ZIP/Postal Code
560017
Country
India
Facility Name
Department of Neurosurgery, National Institute of Mental Health and Neurosciences
City
Bangalore
ZIP/Postal Code
560029
Country
India
Facility Name
Department of Medical Oncology, Nizam's Institute of Medical Sciences
City
Hyderabad
ZIP/Postal Code
500082
Country
India
Facility Name
Department of Neurosurgery, LTMG Hospital & LTM Medical College
City
Mumbai
ZIP/Postal Code
400022
Country
India
Facility Name
Department of Neurosurgery, Neurosciences Center
City
New Dehli
ZIP/Postal Code
110029
Country
India
Facility Name
Department of Neurological Sciences, Christian Medical College & Hospital
City
Vellore
ZIP/Postal Code
632004
Country
India
Facility Name
Soroka Medical Center, Neurosurgery Department
City
Beer Sheva
Country
Israel
Facility Name
Rambam Medical Center, Neurosurgery Department
City
Haifa
ZIP/Postal Code
31096
Country
Israel
Facility Name
Rabin Medical Center, Neurosurgery Department
City
Petach Tikva
ZIP/Postal Code
49100
Country
Israel
Facility Name
Sverdlovsk Regional Oncological Clinic
City
Ekaterinburg
ZIP/Postal Code
620036
Country
Russian Federation
Facility Name
Republican Clinical Hospital of Ministry of Health of Tatarstan Republic
City
Kazan
ZIP/Postal Code
420064
Country
Russian Federation
Facility Name
Burdenko Neurosurgery Research Institute
City
Moscow
ZIP/Postal Code
125047
Country
Russian Federation
Facility Name
Omsk State Medical Academy; State Educational Institution of Higher Professional Education
City
Omsk
ZIP/Postal Code
644099
Country
Russian Federation
Facility Name
State Institution of Healthcare, Samara Regional Clinical Hospital in the name of M.I. Kalinin
City
Samara
ZIP/Postal Code
443095
Country
Russian Federation
Facility Name
Polenov Neurosurgery Research Institute
City
St. Petersburg
ZIP/Postal Code
191104
Country
Russian Federation
Facility Name
Military Medical Academy named after I.S.M. Kirov, Neurosurgery Department
City
St. Petersburg
ZIP/Postal Code
194175
Country
Russian Federation
Facility Name
Medical Center "XXI century"
City
St. Petersburg
ZIP/Postal Code
194354
Country
Russian Federation
Facility Name
Tcheliabinsk Regional Clinical Hospital; State Medical Institution for Prophylaxis and Treatment
City
Tcheliabinsk
ZIP/Postal Code
454076
Country
Russian Federation

12. IPD Sharing Statement

Citations:
PubMed Identifier
31795071
Citation
Uckun FM, Qazi S, Hwang L, Trieu VN. Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFbeta2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up. Cancers (Basel). 2019 Nov 28;11(12):1892. doi: 10.3390/cancers11121892.
Results Reference
derived

Learn more about this trial

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

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