Clinical trial NCT00761280: Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma
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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
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
Lead sponsor: Isarna Therapeutics GmbH
Sponsor class: INDUSTRY
First posted: 2008-09-29
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
timeFrame: 24 months
measure: Survival at 24 Months in the Intent-to-treat Population - Number of Participants
timeFrame: 24 months
Secondary outcomes:
measure: Survival Rate at 12, 18, and 21 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
timeFrame: 12, 18, and 21 months
measure: Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants
timeFrame: 12, 18, and 21 months
measure: Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only)
timeFrame: Up to 24 months
measure: Response Category by Independent Review in the Intent-to-treat Population - Number of Participants
timeFrame: Up to 24 months
measure: Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
timeFrame: Up to 24 months
measure: Tumor Control Rate (CR+PR+SD) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
timeFrame: Up to 24 months
measure: Median Duration of Response (Days) by Independent Review (Descriptive Analysis, Only)
timeFrame: Up to 24 months
measure: Disease Progression at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Number of Participants
timeFrame: 10, 12, 14, 16, 18, 21, and 24 months
measure: Disease Progression Rate at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)
timeFrame: 10, 12, 14, 16, 18, 21 and 24 months
measure: Median Time to Progression (Days) by Independent Review for the Intent-to-treat Population (Descriptive Analysis, Only)
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: Edison
country: United States
facility: NJ Neuroscience Institute; JFK Medical Center
state: New Jersey
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Hospital Británico
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: FLENI
city: Córdoba
country: Argentina
facility: Sanatorio Allende
city: Innsbruck
country: Austria
facility: Universitätsklinik Innsbruck, Abteilung für Neurologie
city: Wien
country: Austria
facility: AKH Wien, Klinik für Neurochirurgie
city: Barretos / SP
country: Brazil
facility: Hospital de Câncer de Barretos
city: Goiania
country: Brazil
facility: Centro Goiano de Oncologia (CGO)
city: Passo Fundo
country: Brazil
facility: Hospital Sao Vicente de Paulo
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Hospital Sao Lucas da PUCRS
city: Sao Paulo
country: Brazil
facility: Hospital do Servidor Público Estadual
city: Chicoutimi
country: Canada
facility: ECOGENE-21 Centre d'études cliniques
state: Quebec
city: Calgary
country: Canada
facility: Foothills Medical Centre
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
city: Marseille
country: France
facility: La Timone University Hospital
city: Frankfurt/M.
country: Germany
facility: Klinik und Poliklinik für Neurochirurgie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Günzburg
country: Germany
facility: Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg
city: Hamburg
country: Germany
facility: Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Neurochirurgische Klinik
city: Heidelberg
country: Germany
facility: Universitätsklinik Heidelberg Neurologische Klinik
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Neurochirurgische Klinik
city: Magdeburg
country: Germany
facility: Otto-von-Guericke-Universität, Klinik für Neurochirurgie
city: Münster
country: Germany
facility: Klinik und Poliklinik für Neurochirurgie
city: Regensburg
country: Germany
facility: Klinik und Poliklinik für Neurologie
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
city: Bangalore
country: India
facility: Manipal Hospital & Manipal Institute for Neurological Disorders
city: Bangalore
country: India
facility: NIMHANS
city: Bangalore
country: India
facility: BGS Global Hospital
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education & Research (PGIMER)
city: Chennai
country: India
facility: Apollo Speciality Hospitals
city: Cochin
country: India
facility: Amrita Institute of Medical Sciences Research Center
city: Hyderabaad
country: India
facility: Care Hospitals
city: Kolkata
country: India
facility: AMRI Hospitals
city: Lucknow
country: India
facility: SGPGI of Medical Sciences
city: Mumbai
country: India
facility: Advanced Centre for Treatment Research and Education in Cancer (ACTREC)
city: New Delhi
country: India
facility: All India Institute of Medical Sciences (AIIMS)
city: Thiruvananthapuram
country: India
facility: SCTIMST, Dept. of Neurosurgery
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University College of Medicine
city: Seoul
country: Korea, Republic of
facility: Kangnam St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Guadalajara
country: Mexico
facility: Hospital San Javier
city: Mexico City
country: Mexico
facility: Hospital General de Mexico
city: Mexico City
country: Mexico
facility: Medica Sur
city: Bydgoszcz
country: Poland
facility: Wojskowy Szpital Kliniczny, Klinika Neurochirurgii
city: Gdańsk
country: Poland
facility: Akademickie Centrum Kliniczne
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 4, Klinika Neurochirurgii i Neurochirurgii Dziecięcej
city: Sosnowiec
country: Poland
facility: Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5
city: Warszawa
country: Poland
facility: Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie
city: Łódź
country: Poland
facility: SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii
city: Chelyabinsk
country: Russian Federation
facility: Chelyabinsk City Hospital #3; Department of Neurosurgery
city: Moscow
country: Russian Federation
facility: State Institution Russian Oncology Research Center N.N. Blokhin
city: Samara
country: Russian Federation
facility: Samara Region Clinical Hospital M.I. Kalinin
city: St. Petersburg
country: Russian Federation
facility: Russian Scientific Research Neurosurgical Institute A.L. Polenov
city: St. Petersburg
country: Russian Federation
facility: Military Medical Academy, Neurosurgery Dept
city: Baracaldo
country: Spain
facility: Hospital de Cruces
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Doce de Octubre
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei City
country: Taiwan
facility: Tri-Service General Hospital
city: Edinburgh
country: United Kingdom
facility: Edinburgh Centre for Neuro-Oncology, Western General Hospital
city: London
country: United Kingdom
facility: The National Hospital for Neurology and Neurosurgery
Study officials:
affiliation: Montreal Neurological Institute and Hospital
name: Rolando Del Maestro, MD, PhD
role: STUDY_CHAIR
References: