Clinical trial NCT00431561: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: Isarna Therapeutics GmbH
Sponsor class: INDUSTRY
First posted: 2007-02-06
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall response rate of two AP 12009 dose groups and control group assessed by the evaluation of tumor size on brain MRI scans
Secondary outcomes:
measure: Overall survival
timeFrame: overall
measure: Overall survival
timeFrame: six- and twelve-month
measure: Response rates
timeFrame: at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable)
measure: Progression-free survival
timeFrame: six-month
measure: Time to progression
measure: Time to response
measure: Best of all response rates assessed by survival status and variation of tumor size on brain MRI
measure: Change of quality of life and Karnofsky Performance Status (KPS)
timeFrame: at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable)
measure: Best of all response rates
measure: Safety and tolerability
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Universitätsklinik Innsbruck; Abteilung für Neurochirurgie
city: Linz
country: Austria
facility: Landes-Nervenklinik Wagner-Jauregg
city: Wien
country: Austria
facility: Kaiser Franz Josef Spital, Abteilung für Neurologie
city: Tbilisi
country: Georgia
facility: Sarajishvili Institute of Clinical Neurology and Neurosurgery
city: Berlin
country: Germany
facility: Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte
city: Cottbus
country: Germany
facility: Klinik und Poliklinik für Neurologie
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen, Neurochirurgische Universitätsklinik
city: Kiel
country: Germany
facility: Universitätsklinikum Kiel, Klinik für Neurochirurgie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie
city: Magdeburg
country: Germany
facility: Universitätsklinik Magdeburg, Klinik für Neurochirurgie
city: Mainz
country: Germany
facility: Universitätskliniken Mainz, Neurochirurgische Klinik und Poliklinik
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Klinik und Poliklinik für Neurochirurgie
city: Regensburg
country: Germany
facility: Klinikum und Poliklinik für Neurologie, Universität Regensburg
city: Saarbrücken
country: Germany
facility: Klinikum Saarbrücken, Neurochirurgie
city: Tübingen
country: Germany
facility: Neurologische Universitätsklinik Tübingen
city: Cochin
country: India
facility: Department of Neurosurgery, Amrita Institute of Medical Sciences & Research Centre
state: Kerala
city: Trivandrum
country: India
facility: Sree Chitra Tirunal Institute for Medical Sciences & Technology, Department of Neurosurgery
state: Kerala
city: Bangalore
country: India
facility: Manipal Hospital; Manipal Institute for Neurological Disorders
city: Bangalore
country: India
facility: Department of Neurosurgery, National Institute of Mental Health and Neurosciences
city: Hyderabad
country: India
facility: Department of Medical Oncology, Nizam's Institute of Medical Sciences
city: Mumbai
country: India
facility: Department of Neurosurgery, LTMG Hospital & LTM Medical College
city: New Dehli
country: India
facility: Department of Neurosurgery, Neurosciences Center
city: Vellore
country: India
facility: Department of Neurological Sciences, Christian Medical College & Hospital
city: Beer Sheva
country: Israel
facility: Soroka Medical Center, Neurosurgery Department
city: Haifa
country: Israel
facility: Rambam Medical Center, Neurosurgery Department
city: Petach Tikva
country: Israel
facility: Rabin Medical Center, Neurosurgery Department
city: Ekaterinburg
country: Russian Federation
facility: Sverdlovsk Regional Oncological Clinic
city: Kazan
country: Russian Federation
facility: Republican Clinical Hospital of Ministry of Health of Tatarstan Republic
city: Moscow
country: Russian Federation
facility: Burdenko Neurosurgery Research Institute
city: Omsk
country: Russian Federation
facility: Omsk State Medical Academy; State Educational Institution of Higher Professional Education
city: Samara
country: Russian Federation
facility: State Institution of Healthcare, Samara Regional Clinical Hospital in the name of M.I. Kalinin
city: St. Petersburg
country: Russian Federation
facility: Polenov Neurosurgery Research Institute
city: St. Petersburg
country: Russian Federation
facility: Military Medical Academy named after I.S.M. Kirov, Neurosurgery Department
city: St. Petersburg
country: Russian Federation
facility: Medical Center "XXI century"
city: Tcheliabinsk
country: Russian Federation
facility: Tcheliabinsk Regional Clinical Hospital; State Medical Institution for Prophylaxis and Treatment
Study officials:
affiliation: University of Regensburg, Dept. of Neurology, Germany
name: Ulrich Bogdahn, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.