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

NCT00761280 | Terminated Phase 3 Results DMC

• 1 other identifier: AP 12009-G005
• Study Type: interventional
• Target: 27
• Locations: 16 countries
• Sites: 68

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).

Conditions

Anaplastic Astrocytoma; Glioblastoma

Keywords

Anaplastic astrocytoma; Glioblastoma; Antisense; Cancer; Transforming Growth Factor beta 2; Targeted therapy; Brain tumor; Glioma; Central Nervous System (CNS); Convection Enhanced Delivery (CED); Intratumoral administration

Outcome Measures

Primary Outcomes (2)

• Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)

  Survival rate was defined as the proportion of participants known to be alive at 24 months from randomization. If a participant's status was unknown and there was no follow-up information available, they were categorized as 'Died' for the purposes of the analysis.

  24 months

• Survival at 24 Months in the Intent-to-treat Population - Number of Participants

  Survival status was assessed at 24 months from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to / insufficient follow-up" includes participants who were alive at last data collection point but did not yet have enough follow-up time to reach the 24 month time point.

  24 months

Secondary Outcomes (10)

• Survival Rate at 12, 18, and 21 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)

  12, 18, and 21 months

• Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants

  12, 18, and 21 months

• Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only)

  Up to 24 months

• Response Category by Independent Review in the Intent-to-treat Population - Number of Participants

  Up to 24 months

• Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)

  Up to 24 months

Study Arms (2)

trabedersen 10 µM

EXPERIMENTAL

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

Drug: trabedersen; Device: Drug delivery system for administration of AP 12009; Procedure: Placement of Drug Delivery System

Chemotherapy

ACTIVE COMPARATOR

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.

Drug: temozolomide; Drug: carmustine; Drug: lomustine

Interventions

trabedersen DRUG

Also known as: AP 12009

trabedersen 10 µM

temozolomide DRUG

Also known as: Temodar, Temodal, TMZ

Chemotherapy

Drug delivery system for administration of AP 12009 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).

trabedersen 10 µM

Placement of Drug Delivery System PROCEDURE

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

trabedersen 10 µM

carmustine DRUG

Also known as: BCNU, BiCNU, Carmubris

Chemotherapy

lomustine DRUG

Also known as: CCNU, CeeNU

Chemotherapy

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Isarna Therapeutics GmbH: lead

Study Sites (68)

NJ Neuroscience Institute; JFK Medical Center

Edison, New Jersey, 08820, United States

Location

Winthrop University Hospital

Mineola, New York, 11501, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Hospital Británico

Buenos Aires, C1280AEB, Argentina

Location

FLENI

Buenos Aires, C1428, Argentina

Location

Sanatorio Allende

Córdoba, X5000JHQ, Argentina

Location

Universitätsklinik Innsbruck, Abteilung für Neurologie

Innsbruck, 6020, Austria

Location

AKH Wien, Klinik für Neurochirurgie

Vienna, 1090, Austria

Location

Hospital de Câncer de Barretos

Barretos / SP, 14784-400, Brazil

Location

Centro Goiano de Oncologia (CGO)

Goiânia, 74223-080, Brazil

Location

Hospital Sao Vicente de Paulo

Passo Fundo, 99010-080, Brazil

Location

Hospital de Clínicas de Porto Alegre

Porto Alegre, 90035-903, Brazil

Location

Hospital Sao Lucas da PUCRS

Porto Alegre, 90610-000, Brazil

Location

Hospital do Servidor Público Estadual

São Paulo, 04038-034, Brazil

Location

ECOGENE-21 Centre d'études cliniques

Chicoutimi, Quebec, G7H 7P2, Canada

Location

Foothills Medical Centre

Calgary, AB T2N 2T9, Canada

Location

Montreal Neurological Institute and Hospital

Montreal, H3A 2B4, Canada

Location

La Timone University Hospital

Marseille, 13385, France

Location

Klinik und Poliklinik für Neurochirurgie

Frankfurt/M., 60528, Germany

Location

Universitätsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg

Günzburg, 89312, Germany

Location

Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie

Hamburg, 20246, Germany

Location

Medizinische Hochschule Hannover Neurochirurgische Klinik

Hanover, 30625, Germany

Location

Universitätsklinik Heidelberg Neurologische Klinik

Heidelberg, 69120, Germany

Location

Universitätsklinikum Leipzig, Neurochirurgische Klinik

Leipzig, 04103, Germany

Location

Otto-von-Guericke-Universität, Klinik für Neurochirurgie

Magdeburg, 39120, Germany

Location

Klinik und Poliklinik für Neurochirurgie

Münster, 48149, Germany

Location

Klinik und Poliklinik für Neurologie

Regensburg, 93053, Germany

Location

Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ

Szeged, 6720, Hungary

Location

Manipal Hospital & Manipal Institute for Neurological Disorders

Bangalore, 560017, India

Location

NIMHANS

Bangalore, 560029, India

Location

BGS Global Hospital

Bangalore, 560060, India

Location

Postgraduate Institute of Medical Education & Research (PGIMER)

Chandigarh, 160012, India

Location

Apollo Speciality Hospitals

Chennai, 600006, India

Location

Care Hospitals

Hyderabaad, 500034, India

Location

Amrita Institute of Medical Sciences Research Center

Kochi, 560017, India

Location

AMRI Hospitals

Kolkata, 700029, India

Location

SGPGI of Medical Sciences

Lucknow, 226014, India

Location

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

Mumbai, 410210, India

Location

All India Institute of Medical Sciences (AIIMS)

New Delhi, 110029, India

Location

SCTIMST, Dept. of Neurosurgery

Thiruvananthapuram, 695011, India

Location

Hospital San Javier

Guadalajara, 44670, Mexico

Location

Hospital General de Mexico

Mexico City, 06120, Mexico

Location

Medica Sur

Mexico City, 14050, Mexico

Location

Wojskowy Szpital Kliniczny, Klinika Neurochirurgii

Bydgoszcz, 85-681, Poland

Location

Akademickie Centrum Kliniczne

Gdansk, 80-952, Poland

Location

SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii

Lodz, 91-153, Poland

Location

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

Lublin, 20-090, Poland

Location

Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5

Sosnowiec, 41-200, Poland

Location

Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie

Warsaw, 02-781, Poland

Location

Chelyabinsk City Hospital #3; Department of Neurosurgery

Chelyabinsk, 454021, Russia

Location

State Institution Russian Oncology Research Center N.N. Blokhin

Moscow, 115478, Russia

Location

Russian Scientific Research Neurosurgical Institute A.L. Polenov

Saint Petersburg, 191104, Russia

Location

Military Medical Academy, Neurosurgery Dept

Saint Petersburg, 194044, Russia

Location

Samara Region Clinical Hospital M.I. Kalinin

Samara, 443095, Russia

Location

Severance Hospital, Yonsei University College of Medicine

Seoul, 120-752, South Korea

Location

Kangnam St. Mary's Hospital

Seoul, 137-701, South Korea

Location

Asan Medical Center

Seoul, 138-736, South Korea

Location

Hospital de Cruces

Barakaldo, 48903, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Doce de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario Marqués de Valdecilla

Santander, 39008, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

China Medical University Hospital

Taichung, 404, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 407, Taiwan

Location

Tri-Service General Hospital

Taipei, 114, Taiwan

Location

Edinburgh Centre for Neuro-Oncology, Western General Hospital

Edinburgh, EH42XU, United Kingdom

Location

The National Hospital for Neurology and Neurosurgery

London, WC1N 3BG, United Kingdom

Location

MeSH Terms

Conditions

Astrocytoma; Glioblastoma; Neoplasms; Brain Neoplasms; Glioma

Interventions

Trabedersen; Temozolomide; Drug Delivery Systems; Carmustine; Lomustine

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Therapy; Therapeutics; Nitrosourea Compounds; Urea; Amides; Nitroso Compounds

Limitations and Caveats

Early termination of the study leading to recruitment of 27 of 180 planned subjects and incomplete collection of data. Survival results are based on post-study collection of additional survival data under a protocol amendment.

Results Point of Contact

• Title: Medical Officer
• Organization: Isarna Therapeutics GmbH, formerly Antisense Pharma GmbH

info@isarna-therapeutics.com

+49-89-890831

Study Officials

• Rolando Del Maestro, MD, PhD

  Montreal Neurological Institute and Hospital

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2008
• First Posted: September 29, 2008
• Study Start: December 1, 2008
• Primary Completion: February 1, 2012
• Study Completion: June 1, 2012
• Last Updated: November 14, 2014
• Results First Posted: August 22, 2014

Record last verified: 2014-11

Locations

BR (6); TW (3); AR (3); AU (2); CA (3); ES (5); DE (10); PL (6); RU (5); KR (3); US (3); GB (2); FR (1); HU (1); IN (12); ME (3)