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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00431561
Recruitment Status : Completed
First Posted : February 6, 2007
Last Update Posted : December 3, 2013
Sponsor:
Information provided by:
Isarna Therapeutics GmbH

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.

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Study Type : Interventional  (Clinical Trial)
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 : April 2003
Actual Primary Completion Date : March 2009
Actual Study Completion Date : March 2009


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




Primary Outcome Measures :
  1. 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 :
  1. Overall survival [ Time Frame: overall ]
  2. Overall survival [ Time Frame: six- and twelve-month ]
  3. Response rates [ Time Frame: at 3, 8, 10, and 12 months (and during the prolonged follow-up period in six-monthly intervals, if applicable) ]
  4. Progression-free survival [ Time Frame: six-month ]
  5. Time to progression
  6. Time to response
  7. Best of all response rates assessed by survival status and variation of tumor size on brain MRI
  8. 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) ]
  9. Best of all response rates
  10. Safety and tolerability


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00431561


Locations
Show Show 36 study locations
Sponsors and Collaborators
Isarna Therapeutics GmbH
Investigators
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Principal Investigator: Ulrich Bogdahn, MD University of Regensburg, Dept. of Neurology, Germany
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hubert Heinrichs, MD, PhD, Chief Medical Officer, Antisense Pharma
ClinicalTrials.gov Identifier: NCT00431561    
Other Study ID Numbers: AP 12009-G004
First Posted: February 6, 2007    Key Record Dates
Last Update Posted: December 3, 2013
Last Verified: December 2013
Keywords provided by Isarna Therapeutics GmbH:
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
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Lomustine
Trabedersen
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents