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

Sponsor

Isarna Therapeutics GmbH (Industry)

Overall Status

Completed

CT.gov ID

NCT00431561

Collaborator

(none)

141

Enrollment

Locations

Arms

Duration (Months)

3.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Anaplastic Astrocytoma	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	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

141 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Apr 1, 2003

Actual Primary Completion Date :

Mar 1, 2009

Actual Study Completion Date :

Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AP 12009 10 µM	Drug: AP 12009 10 µM 10 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks 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.
Experimental: AP 12009 80 µM	Drug: AP 12009 80 µM 80 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks 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.
Active Comparator: Chemotherapy	Drug: temozolomide or PCV temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle; PCV (procarbazine, CCNU, vincristine): standard regimen Other Names: Temodar Temodal TMZ lomustine Cecenu CeeNU

Arm

Intervention/Treatment

Experimental: AP 12009 10 µM

Drug: AP 12009 10 µM

10 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks

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.

Experimental: AP 12009 80 µM

Drug: AP 12009 80 µM

80 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks

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.

Active Comparator: Chemotherapy

Drug: temozolomide or PCV

temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle; PCV (procarbazine, CCNU, vincristine): standard regimen

Other Names:

Temodar

Temodal

TMZ

lomustine

Cecenu

CeeNU

Outcome Measures

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]
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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitätsklinik Innsbruck; Abteilung für Neurochirurgie	Innsbruck		Austria	6020
2	Landes-Nervenklinik Wagner-Jauregg	Linz		Austria	4020
3	Kaiser Franz Josef Spital, Abteilung für Neurologie	Wien		Austria	1100
4	Sarajishvili Institute of Clinical Neurology and Neurosurgery	Tbilisi		Georgia	0114
5	Medizinische Klinik und Poliklinik mit Schwerpunkt Onkologie und Hämatologie, Charité Campus Mitte	Berlin		Germany	10117
6	Klinik und Poliklinik für Neurologie	Cottbus		Germany	03048
7	Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden	Dresden		Germany	01307
8	Universitätsklinikum Gießen, Neurochirurgische Universitätsklinik	Gießen		Germany	35392
9	Universitätsklinikum Kiel, Klinik für Neurochirurgie	Kiel		Germany	24106
10	Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurochirurgie	Leipzig		Germany	04103
11	Universitätsklinik Magdeburg, Klinik für Neurochirurgie	Magdeburg		Germany	39120
12	Universitätskliniken Mainz, Neurochirurgische Klinik und Poliklinik	Mainz		Germany	55131
13	Universitätsklinikum Münster, Klinik und Poliklinik für Neurochirurgie	Münster		Germany	48149
14	Klinikum und Poliklinik für Neurologie, Universität Regensburg	Regensburg		Germany	93053
15	Klinikum Saarbrücken, Neurochirurgie	Saarbrücken		Germany	66119
16	Neurologische Universitätsklinik Tübingen	Tübingen		Germany	72076
17	Department of Neurosurgery, Amrita Institute of Medical Sciences & Research Centre	Cochin	Kerala	India	682026
18	Sree Chitra Tirunal Institute for Medical Sciences & Technology, Department of Neurosurgery	Trivandrum	Kerala	India	695011
19	Manipal Hospital; Manipal Institute for Neurological Disorders	Bangalore		India	560017
20	Department of Neurosurgery, National Institute of Mental Health and Neurosciences	Bangalore		India	560029
21	Department of Medical Oncology, Nizam's Institute of Medical Sciences	Hyderabad		India	500082
22	Department of Neurosurgery, LTMG Hospital & LTM Medical College	Mumbai		India	400022
23	Department of Neurosurgery, Neurosciences Center	New Dehli		India	110029
24	Department of Neurological Sciences, Christian Medical College & Hospital	Vellore		India	632004
25	Soroka Medical Center, Neurosurgery Department	Beer Sheva		Israel
26	Rambam Medical Center, Neurosurgery Department	Haifa		Israel	31096
27	Rabin Medical Center, Neurosurgery Department	Petach Tikva		Israel	49100
28	Sverdlovsk Regional Oncological Clinic	Ekaterinburg		Russian Federation	620036
29	Republican Clinical Hospital of Ministry of Health of Tatarstan Republic	Kazan		Russian Federation	420064
30	Burdenko Neurosurgery Research Institute	Moscow		Russian Federation	125047
31	Omsk State Medical Academy; State Educational Institution of Higher Professional Education	Omsk		Russian Federation	644099
32	State Institution of Healthcare, Samara Regional Clinical Hospital in the name of M.I. Kalinin	Samara		Russian Federation	443095
33	Polenov Neurosurgery Research Institute	St. Petersburg		Russian Federation	191104
34	Military Medical Academy named after I.S.M. Kirov, Neurosurgery Department	St. Petersburg		Russian Federation	194175
35	Medical Center "XXI century"	St. Petersburg		Russian Federation	194354
36	Tcheliabinsk Regional Clinical Hospital; State Medical Institution for Prophylaxis and Treatment	Tcheliabinsk		Russian Federation	454076