Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma

NCT ID: NCT00761280

Last Updated: 2014-11-14

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 27 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-12-31
• Study Completion Date: 2012-06-30

Brief Summary

In this multinational Phase III study the efficacy and safety of 10 µM AP 12009 is compared to standard chemotherapy (temozolomide or BCNU or CCNU) in adult patients with confirmed recurrent or refractory anaplastic astrocytoma (WHO grade III) or secondary glioblastoma (WHO grade IV).

Detailed Description

The purpose of this study is to compare the safety and efficacy of the 10 µM concentration of AP 12009 and standard chemotherapy (temozolomide, BCNU, CCNU) in adult patients with recurrent or refractory anaplastic astrocytoma (AA, WHO grade III) or secondary glioblastoma (GBM, WHO grade IV). AP 12009 (trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human Transforming Growth Factor beta 2 (TGF-beta-2), which is applied intratumorally. 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. In patients with high-grade glioma, the TGF-beta-2 overexpression is associated with disease stage, clinical prognosis, and the immunodeficient state of the patients. Main objective of the study is to determine survival (rate) and tumor response.

Important note: Due to early trial termination, resulting in limited data availability, all analyses remain descriptive by nature, only. No conclusive endpoint analysis can be performed.

Conditions

Anaplastic Astrocytoma; Glioblastoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

trabedersen 10 µM

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

Group Type: EXPERIMENTAL

trabedersen

Intervention Type: DRUG

Drug delivery system for administration of AP 12009

Intervention Type: DEVICE

Drug delivery system for Convection Enhanced Delivery consists of a portable pump (Pegasus vario or Pega vario) with drug reservoir (Pega Bag) and infusion line (Pega Line). Main implanted parts are the port access system (PORT-A-CATH) and the intratumoral catheter (Medtronic ventricular catheter).

Placement of Drug Delivery System

Intervention Type: PROCEDURE

Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.

Chemotherapy

temozolomide: capsules, up to 200 mg/sqm/day, 5 days per cycle, up to 26 cycles; carmustine: i.v. administration, up to 200 mg/sqm/day, 1 day per cycle, up to 8 cycles; lomustine: capsules, 110 mg/sqm/day, 1 day per cycle, up to 8 cycles. Only 1 of these 3 drugs/interventions is administered per patient in the comparator arm.

Group Type: ACTIVE_COMPARATOR

temozolomide

Intervention Type: DRUG

carmustine

Intervention Type: DRUG

lomustine

Intervention Type: DRUG

Interventions

trabedersen

Intervention Type: DRUG

temozolomide

Intervention Type: DRUG

Drug delivery system for administration of AP 12009

Drug delivery system for Convection Enhanced Delivery consists of a portable pump (Pegasus vario or Pega vario) with drug reservoir (Pega Bag) and infusion line (Pega Line). Main implanted parts are the port access system (PORT-A-CATH) and the intratumoral catheter (Medtronic ventricular catheter).

Intervention Type: DEVICE

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.

Intervention Type: PROCEDURE

carmustine

Intervention Type: DRUG

lomustine

Intervention Type: DRUG

Other Intervention Names

AP 12009; Temodar; Temodal; TMZ; BCNU; BiCNU; Carmubris; CCNU; CeeNU

Eligibility Criteria

Inclusion Criteria

• The patient has provided written informed consent prior to any study-related procedure.
• The patient is at least 18 years of age and equal to or below 70 years.
• The patient has a present diagnosis of AA or secondary GBM.
• The patient has a measurable lesion (> 1 ccm in volume, central MRI review).
• The lesion (or sum of lesions) does not exceed 50 ccm in volume (central MRI review).
• The tumor is localized supratentorially (central MRI review).
• All patients have recurrent or refractory disease, i.e. disease has progressed after prior surgery and radiotherapy at any time of the disease course or stage. Secondary GBM patients have progressed after a previous diagnosis of A and/or AA.
• The patient has not received more than one chemotherapy regimen. Radiation with concomitant chemotherapy, followed by adjuvant chemotherapy, is considered as one chemotherapy regimen.
• The patient is eligible for chemotherapy.
• The patient is on a maximum dose of 4 mg/day dexamethasone or equivalent doses for other corticosteroids, which has been stable or decreasing for at least 3 weeks prior to Screening.
• The patient is male or a non-pregnant, non-lactating female.
• Females of childbearing potential must have a negative beta-HCG pregnancy test at Screening.
• Females of childbearing potential and males must practice strict birth control.
• The patient must have recovered from acute toxicity caused by any previous therapy.
• The patient has a life expectancy of at least 3 months.
• The patient has a Karnofsky Performance Status of at least 70%.
• The patient shows adequate organ functions as assessed by the following screening laboratory values:

1. Adequate renal function determined by serum creatinine and urea < 2 times the upper limit of normal

2. Adequate liver function with ALT, AST and AP < 3 times the upper limit of normal, and bilirubin < 2.5 mg/dL

3. INR < 1.5 and aPTT < 1.5 x ULN

4. Hemoglobin > 9 g/dL

5. Platelet count > 100 x 10E9/L

6. WBC > 3 x 10E9/L

7. ANC > 1.5 x 10E9/L (or WBC > 3.0 x 10E9/L)

Exclusion Criteria

• Patient unable or not willing to comply with the protocol regulations.
• The investigator deems it necessary to surgically (re-)resect the present tumor (NOTE: the patient might still be eligible for randomization at a later timepoint).
• Tumor surgery, tumor debulking, or other neurosurgery within 3 months prior to randomization. If a ≤48-hour routine post-surgery MRI (in accordance with study specifications) qualifies the patient for study participation, the patient can be randomized 30 ± 7 days post-surgery.
• Radiotherapy or stereotactic (gamma knife) radiosurgery within 3 months prior to randomization.
• Prior interstitial brachytherapy of the brain with permanent implants. Prior interstitial brachytherapy of the brain with removable implants within 3 months prior to randomization.
• Chemotherapy, hormone therapy, or any other therapy with established or suggested anti-tumor effects within 4 weeks (nitrosoureas: 6 weeks) prior to randomization.
• Prior anti-TGF-beta 2 targeted therapy.
• Screening MRI shows a mass effect caused by the tumor defined as significant compression of the ventricular system and/or a midline shift (≥ 3 mm, central MRI review). Compression of the ventricular system and/or a midline shift ≥ 3 mm only due to the presence of (a) cyst(s) or scarring processes does not exclude an individual from the study.
• Participation in another clinical study with another investigational medicinal product within 30 days prior to randomization.
• History of a second independent malignant disorder within 5 years, except for carcinoma in situ of the cervix and basal cell carcinoma.
• Presence of poorly controlled seizures.
• Clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, unstable angina, or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to randomization.
• Known HIV, HBV or HCV infection.
• Acute viral, bacterial, or fungal infection.
• Acute medical problems that may be considered to become an unacceptable risk, or any conditions, which might be contraindications for starting study treatment.
• Presence of high risk for pulmonary toxicities, defined as:

1. Lung function: vital capacity ≤ 70%

2. Status following sequential or concomitant thoracic irradiation

3. Increased risk for a pulmonary toxicity induced by BCNU (Carmustine) or CCNU (Lomustine). Risk factors include smoking, presence of a respiratory condition, pre-existing radiographic pulmonary abnormalities, exposure to agents that cause lung damage.

• History of allergies to reagents used in this study, history of celiac disease.
• Drug abuse or extensive use of alcohol.
• Clinically relevant psychiatric disorders / legal incapacity or a limited legal capacity.
• Concomitant treatment with yellow fever vaccine.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Isarna Therapeutics GmbH

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rolando Del Maestro, MD, PhD

Role: STUDY_CHAIR

Montreal Neurological Institute and Hospital

Locations

NJ Neuroscience Institute; JFK Medical Center

Edison, New Jersey, United States

Winthrop University Hospital

Mineola, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Hospital Británico

Buenos Aires, , Argentina

FLENI

Buenos Aires, , Argentina

Sanatorio Allende

Córdoba, , Argentina

Universitätsklinik Innsbruck, Abteilung für Neurologie

Innsbruck, , Austria

AKH Wien, Klinik für Neurochirurgie

Vienna, , Austria

Hospital de Câncer de Barretos

Barretos / SP, , Brazil

Centro Goiano de Oncologia (CGO)

Goiânia, , Brazil

Hospital Sao Vicente de Paulo

Passo Fundo, , Brazil

Hospital de Clínicas de Porto Alegre

Porto Alegre, , Brazil

Hospital Sao Lucas da PUCRS

Porto Alegre, , Brazil

Hospital do Servidor Público Estadual

São Paulo, , Brazil

ECOGENE-21 Centre d'études cliniques

Chicoutimi, Quebec, Canada

Foothills Medical Centre

Calgary, , Canada

Montreal Neurological Institute and Hospital

Montreal, , Canada

La Timone University Hospital

Marseille, , France

Klinik und Poliklinik für Neurochirurgie

Frankfurt/M., , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg

Günzburg, , Germany

Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie

Hamburg, , Germany

Medizinische Hochschule Hannover Neurochirurgische Klinik

Hanover, , Germany

Universitätsklinik Heidelberg Neurologische Klinik

Heidelberg, , Germany

Universitätsklinikum Leipzig, Neurochirurgische Klinik

Leipzig, , Germany

Otto-von-Guericke-Universität, Klinik für Neurochirurgie

Magdeburg, , Germany

Klinik und Poliklinik für Neurochirurgie

Münster, , Germany

Klinik und Poliklinik für Neurologie

Regensburg, , Germany

Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ

Szeged, , Hungary

Manipal Hospital & Manipal Institute for Neurological Disorders

Bangalore, , India

NIMHANS

Bangalore, , India

BGS Global Hospital

Bangalore, , India

Postgraduate Institute of Medical Education & Research (PGIMER)

Chandigarh, , India

Apollo Speciality Hospitals

Chennai, , India

Care Hospitals

Hyderabaad, , India

Amrita Institute of Medical Sciences Research Center

Kochi, , India

AMRI Hospitals

Kolkata, , India

SGPGI of Medical Sciences

Lucknow, , India

Advanced Centre for Treatment Research and Education in Cancer (ACTREC)

Mumbai, , India

All India Institute of Medical Sciences (AIIMS)

New Delhi, , India

SCTIMST, Dept. of Neurosurgery

Thiruvananthapuram, , India

Hospital San Javier

Guadalajara, , Mexico

Hospital General de Mexico

Mexico City, , Mexico

Medica Sur

Mexico City, , Mexico

Wojskowy Szpital Kliniczny, Klinika Neurochirurgii

Bydgoszcz, , Poland

Akademickie Centrum Kliniczne

Gdansk, , Poland

SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii

Lodz, , Poland

Samodzielny Publiczny Szpital Kliniczny nr 4, Klinika Neurochirurgii i Neurochirurgii Dziecięcej

Lublin, , Poland

Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5

Sosnowiec, , Poland

Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie

Warsaw, , Poland

Chelyabinsk City Hospital #3; Department of Neurosurgery

Chelyabinsk, , Russia

State Institution Russian Oncology Research Center N.N. Blokhin

Moscow, , Russia

Russian Scientific Research Neurosurgical Institute A.L. Polenov

Saint Petersburg, , Russia

Military Medical Academy, Neurosurgery Dept

Saint Petersburg, , Russia

Samara Region Clinical Hospital M.I. Kalinin

Samara, , Russia

Severance Hospital, Yonsei University College of Medicine

Seoul, , South Korea

Kangnam St. Mary's Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Hospital de Cruces

Barakaldo, , Spain

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital Doce de Octubre

Madrid, , Spain

Hospital Universitario Marqués de Valdecilla

Santander, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

China Medical University Hospital

Taichung, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

Tri-Service General Hospital

Taipei, , Taiwan

Edinburgh Centre for Neuro-Oncology, Western General Hospital

Edinburgh, , United Kingdom

The National Hospital for Neurology and Neurosurgery

London, , United Kingdom

Countries

United States; Argentina; Austria; Brazil; Canada; France; Germany; Hungary; India; Mexico; Poland; Russia; South Korea; Spain; Taiwan; United Kingdom

Other Identifiers

AP 12009-G005

Identifier Type: -

Identifier Source: org_study_id