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

Glioblastoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00431561
• Other study ID #: AP 12009-G004
• Status: Completed
• Phase: Phase 2
• First received: February 5, 2007
• Last updated: December 2, 2013
• Start date: April 2003
• Est. completion date: March 2009

Study information

• Verified date: December 2013
• Source: Isarna Therapeutics GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Federal Ministry for Health and WomenGeorgia: Ministry of HealthGermany: Federal Institute for Drugs and Medical DevicesIndia: Ministry of HealthIsrael: Ministry of HealthRussia: Pharmacological Committee, Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: March 2009
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Astrocytoma
• Glioblastoma

Intervention

Drug:
• AP 12009 10 µM
10 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
• AP 12009 80 µM
80 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
• temozolomide or PCV
temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle; PCV (procarbazine, CCNU, vincristine): standard regimen

Device:
• Drug delivery system for administration of AP 12009
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.

Procedure:
• Placement of Drug Delivery System
Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.

Locations

Country	Name	City	State
Austria	Universitätsklinik Innsbruck; Abteilung für Neurochirurgie	Innsbruck
Austria	Landes-Nervenklinik Wagner-Jauregg	Linz
Austria	Kaiser Franz Josef Spital, Abteilung für Neurologie	Wien
Georgia	Sarajishvili Institute of Clinical Neurology and Neurosurgery	Tbilisi
Germany	Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte	Berlin
Germany	Klinik und Poliklinik für Neurologie	Cottbus
Germany	Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden	Dresden
Germany	Universitätsklinikum Gießen, Neurochirurgische Universitätsklinik	Gießen
Germany	Universitätsklinikum Kiel, Klinik für Neurochirurgie	Kiel
Germany	Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie	Leipzig
Germany	Universitätsklinik Magdeburg, Klinik für Neurochirurgie	Magdeburg
Germany	Universitätskliniken Mainz, Neurochirurgische Klinik und Poliklinik	Mainz
Germany	Universitätsklinikum Münster, Klinik und Poliklinik für Neurochirurgie	Münster
Germany	Klinikum und Poliklinik für Neurologie, Universität Regensburg	Regensburg
Germany	Klinikum Saarbrücken, Neurochirurgie	Saarbrücken
Germany	Neurologische Universitätsklinik Tübingen	Tübingen
India	Department of Neurosurgery, National Institute of Mental Health and Neurosciences	Bangalore
India	Manipal Hospital; Manipal Institute for Neurological Disorders	Bangalore
India	Department of Neurosurgery, Amrita Institute of Medical Sciences & Research Centre	Cochin	Kerala
India	Department of Medical Oncology, Nizam's Institute of Medical Sciences	Hyderabad
India	Department of Neurosurgery, LTMG Hospital & LTM Medical College	Mumbai
India	Department of Neurosurgery, Neurosciences Center	New Dehli
India	Sree Chitra Tirunal Institute for Medical Sciences & Technology, Department of Neurosurgery	Trivandrum	Kerala
India	Department of Neurological Sciences, Christian Medical College & Hospital	Vellore
Israel	Soroka Medical Center, Neurosurgery Department	Beer Sheva
Israel	Rambam Medical Center, Neurosurgery Department	Haifa
Israel	Rabin Medical Center, Neurosurgery Department	Petach Tikva
Russian Federation	Sverdlovsk Regional Oncological Clinic	Ekaterinburg
Russian Federation	Republican Clinical Hospital of Ministry of Health of Tatarstan Republic	Kazan
Russian Federation	Burdenko Neurosurgery Research Institute	Moscow
Russian Federation	Omsk State Medical Academy; State Educational Institution of Higher Professional Education	Omsk
Russian Federation	State Institution of Healthcare, Samara Regional Clinical Hospital in the name of M.I. Kalinin	Samara
Russian Federation	Medical Center "XXI century"	St. Petersburg
Russian Federation	Military Medical Academy named after I.S.M. Kirov, Neurosurgery Department	St. Petersburg
Russian Federation	Polenov Neurosurgery Research Institute	St. Petersburg
Russian Federation	Tcheliabinsk Regional Clinical Hospital; State Medical Institution for Prophylaxis and Treatment	Tcheliabinsk

Sponsors (1)

Lead Sponsor	Collaborator
Isarna Therapeutics GmbH

Countries where clinical trial is conducted

Austria,  Georgia,  Germany,  India,  Israel,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response rate of two AP 12009 dose groups and control group assessed by the evaluation of tumor size on brain MRI scans			No
Secondary	Overall survival		overall	No
Secondary	Overall survival		six- and twelve-month	No
Secondary	Response rates		at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable)	No
Secondary	Progression-free survival		six-month	No
Secondary	Time to progression			No
Secondary	Time to response			No
Secondary	Best of all response rates assessed by survival status and variation of tumor size on brain MRI			No
Secondary	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)	No
Secondary	Best of all response rates			No
Secondary	Safety and tolerability			Yes