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

This study has been terminated.
(Stopped due to lack of patients (no safety or efficacy issues). Reasons: Changed WHO brain tumor definitions, standard of care 1st line, neurosurgical advances.)
Sponsor:
Information provided by (Responsible Party):
Isarna Therapeutics GmbH
ClinicalTrials.gov Identifier:
NCT00761280
First received: September 26, 2008
Last updated: October 22, 2013
Last verified: October 2013
  Purpose

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).


Condition Intervention Phase
Anaplastic Astrocytoma
Glioblastoma
Drug: trabedersen
Drug: temozolomide
Device: Drug delivery system for administration of AP 12009
Procedure: Placement of Drug Delivery System
Drug: carmustine
Drug: lomustine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Efficacy and Safety of AP 12009 in Adult Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma as Compared to Standard Chemotherapy Treatment: A Randomized, Actively Controlled, Open Label Clinical Phase III Study.

Resource links provided by NLM:


Further study details as provided by Isarna Therapeutics GmbH:

Primary Outcome Measures:
  • Survival rate [ Time Frame: 24 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression rate [ Time Frame: 10, 12, 14, 16, 18, 21, and 24 months ] [ Designated as safety issue: No ]
  • Time to death (months) [ Designated as safety issue: No ]
  • Overall response rate [ Designated as safety issue: No ]
  • Tumor control rate [ Designated as safety issue: No ]
  • Duration of response [ Designated as safety issue: No ]
  • Time to progression (months) [ Designated as safety issue: No ]
  • Survival rate [ Time Frame: 12, 18, 21, 27, and 30 months; 3 and 4 years ] [ Designated as safety issue: No ]
  • Quality of Life (EORTC QLQ-C30, Independent Living Score [ILS]) [ Designated as safety issue: No ]

Enrollment: 27
Study Start Date: December 2008
Study Completion Date: June 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: trabedersen 10 µM
10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Drug: trabedersen
Other Name: AP 12009
Device: 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).
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
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
Other Names:
  • Temodar
  • Temodal
  • TMZ
Drug: carmustine
Other Names:
  • BCNU
  • BiCNU
  • Carmubris
Drug: lomustine
Other Names:
  • CCNU
  • CeeNU

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00761280

  Hide Study Locations
Locations
United States, New Jersey
NJ Neuroscience Institute; JFK Medical Center
Edison, New Jersey, United States, 08820
United States, New York
Winthrop University Hospital
Mineola, New York, United States, 11501
University of Rochester Medical Center
Rochester, New York, United States, 14642
Argentina
Hospital Británico
Ciudad Autónoma de Buenos Aires, Argentina, C1280AEB
FLENI
Ciudad Autónoma de Buenos Aires, Argentina, C1428
Sanatorio Allende
Córdoba, Argentina, X5000JHQ
Austria
Universitätsklinik Innsbruck, Abteilung für Neurologie
Innsbruck, Austria, 6020
AKH Wien, Klinik für Neurochirurgie
Wien, Austria, 1090
Brazil
Hospital de Câncer de Barretos
Barretos / SP, Brazil, 14784-400
Centro Goiano de Oncologia (CGO)
Goiania, Brazil, 74223-080
Hospital Sao Vicente de Paulo
Passo Fundo, Brazil, 99010-080
Hospital de Clínicas de Porto Alegre
Porto Alegre, Brazil, 90035-903
Hospital Sao Lucas da PUCRS
Porto Alegre, Brazil, 90610-000
Hospital do Servidor Público Estadual
Sao Paulo, Brazil, 04038-034
Canada, Quebec
ECOGENE-21 Centre d'études cliniques
Chicoutimi, Quebec, Canada, G7H 7P2
Canada
Foothills Medical Centre
Calgary, Canada, AB T2N 2T9
Montreal Neurological Institute and Hospital
Montreal, Canada, H3A 2B4
France
La Timone University Hospital
Marseille, France, 13385
Germany
Klinik und Poliklinik für Neurochirurgie
Frankfurt/M., Germany, 60528
Universitätsklinikum Freiburg
Freiburg, Germany, 79106
Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg
Günzburg, Germany, 89312
Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie
Hamburg, Germany, 20246
Medizinische Hochschule Hannover Neurochirurgische Klinik
Hannover, Germany, 30625
Universitätsklinik Heidelberg Neurologische Klinik
Heidelberg, Germany, 69120
Universitätsklinikum Leipzig, Neurochirurgische Klinik
Leipzig, Germany, 04103
Otto-von-Guericke-Universität, Klinik für Neurochirurgie
Magdeburg, Germany, 39120
Klinik und Poliklinik für Neurochirurgie
Münster, Germany, 48149
Klinik und Poliklinik für Neurologie
Regensburg, Germany, 93053
Hungary
Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
Szeged, Hungary, 6720
India
BGS Global Hospital
Bangalore, India, 560060
Manipal Hospital & Manipal Institute for Neurological Disorders
Bangalore, India, 560017
NIMHANS
Bangalore, India, 560029
Postgraduate Institute of Medical Education & Research (PGIMER)
Chandigarh, India, 160012
Apollo Speciality Hospitals
Chennai, India, 600006
Amrita Institute of Medical Sciences Research Center
Cochin, India, 560017
Care Hospitals
Hyderabaad, India, 500034
AMRI Hospitals
Kolkata, India, 700029
SGPGI of Medical Sciences
Lucknow, India, 226014
Advanced Centre for Treatment Research and Education in Cancer (ACTREC)
Mumbai, India, 410210
All India Institute of Medical Sciences (AIIMS)
New Delhi, India, 110029
SCTIMST, Dept. of Neurosurgery
Thiruvananthapuram, India, 695011
Korea, Republic of
Severance Hospital, Yonsei University College of Medicine
Seoul, Korea, Republic of, 120-752
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Kangnam St. Mary's Hospital
Seoul, Korea, Republic of, 137-701
Mexico
Hospital San Javier
Guadalajara, Mexico, 44670
Medica Sur
Mexico City, Mexico, 14050
Hospital General de Mexico
Mexico City, Mexico, 06120
Poland
Wojskowy Szpital Kliniczny, Klinika Neurochirurgii
Bydgoszcz, Poland, 85-681
Akademickie Centrum Kliniczne
Gdańsk, Poland, 80-952
Samodzielny Publiczny Szpital Kliniczny nr 4, Klinika Neurochirurgii i Neurochirurgii Dziecięcej
Lublin, Poland, 20-090
Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5
Sosnowiec, Poland, 41-200
Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie
Warszawa, Poland, 02-781
SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii
Łódź, Poland, 91-153
Russian Federation
Chelyabinsk City Hospital #3; Department of Neurosurgery
Chelyabinsk, Russian Federation, 454021
State Institution Russian Oncology Research Center N.N. Blokhin
Moscow, Russian Federation, 115478
Samara Region Clinical Hospital M.I. Kalinin
Samara, Russian Federation, 443095
Military Medical Academy, Neurosurgery Dept
St. Petersburg, Russian Federation, 194044
Russian Scientific Research Neurosurgical Institute A.L. Polenov
St. Petersburg, Russian Federation, 191104
Spain
Hospital de Cruces
Baracaldo, Spain, 48903
Hospital Universitario Vall d'Hebron
Barcelona, Spain, 08035
Hospital Doce de Octubre
Madrid, Spain, 28041
Hospital Universitario Marqués de Valdecilla
Santander, Spain, 39008
Hospital Universitario Virgen del Rocío
Sevilla, Spain, 41013
Taiwan
China Medical University Hospital
Taichung, Taiwan, 404
Taichung Veterans General Hospital
Taichung, Taiwan, 407
Tri-Service General Hospital
Taipei City, Taiwan, 114
United Kingdom
Edinburgh Centre for Neuro-Oncology, Western General Hospital
Edinburgh, United Kingdom, EH42XU
The National Hospital for Neurology and Neurosurgery
London, United Kingdom, WC1N 3BG
Sponsors and Collaborators
Isarna Therapeutics GmbH
Investigators
Study Chair: Rolando Del Maestro, MD, PhD Montreal Neurological Institute and Hospital
  More Information

No publications provided

Responsible Party: Isarna Therapeutics GmbH
ClinicalTrials.gov Identifier: NCT00761280     History of Changes
Other Study ID Numbers: AP 12009-G005
Study First Received: September 26, 2008
Last Updated: October 22, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Austria: Federal Office for Safety in Health Care
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Israel: Ethics Commission
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Spain: Spanish Agency of Medicines
Russia: Ministry of Health of the Russian Federation
United Kingdom: Medicines and Healthcare Products Regulatory Agency
India: Drugs Controller General of India
Mexico: Federal Commission for Sanitary Risks Protection
Brazil: National Health Surveillance Agency
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Hungary: National Institute of Pharmacy
South Korea: Korea Food and Drug Administration (KFDA)
Taiwan : Food and Drug Administration

Keywords provided by Isarna Therapeutics GmbH:
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

Additional relevant MeSH terms:
Astrocytoma
Glioblastoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Carmustine
Lomustine
Temozolomide
Trabedersen
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 17, 2014