Clinical Trials Logo

Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT00761280
Other study ID # AP 12009-G005
Secondary ID
Status Terminated
Phase Phase 3
First received September 26, 2008
Last updated November 4, 2014
Start date December 2008
Est. completion date June 2012

Study information

Verified date November 2014
Source Isarna Therapeutics GmbH
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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).


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.


Recruitment information / eligibility

Status Terminated
Enrollment 27
Est. completion date June 2012
Est. primary completion date February 2012
Accepts healthy volunteers No
Gender All
Age group 18 Years to 70 Years
Eligibility 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.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
trabedersen

temozolomide

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.
Drug:
carmustine

lomustine


Locations

Country Name City State
Argentina FLENI Ciudad Autónoma de Buenos Aires
Argentina Hospital Británico Ciudad Autónoma de Buenos Aires
Argentina Sanatorio Allende Córdoba
Austria Universitätsklinik Innsbruck, Abteilung für Neurologie Innsbruck
Austria AKH Wien, Klinik für Neurochirurgie Wien
Brazil Hospital de Câncer de Barretos Barretos / SP
Brazil Centro Goiano de Oncologia (CGO) Goiania
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 Sao Paulo
Canada Foothills Medical Centre Calgary
Canada ECOGENE-21 Centre d'études cliniques Chicoutimi Quebec
Canada Montreal Neurological Institute and Hospital Montreal
France La Timone University Hospital Marseille
Germany Klinik und Poliklinik für Neurochirurgie Frankfurt/M.
Germany Universitätsklinikum Freiburg Freiburg
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 Hannover
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
Hungary Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ Szeged
India BGS Global Hospital Bangalore
India Manipal Hospital & Manipal Institute for Neurological Disorders Bangalore
India NIMHANS Bangalore
India Postgraduate Institute of Medical Education & Research (PGIMER) Chandigarh
India Apollo Speciality Hospitals Chennai
India Amrita Institute of Medical Sciences Research Center Cochin
India Care Hospitals Hyderabaad
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
Korea, Republic of Asan Medical Center Seoul
Korea, Republic of Kangnam St. Mary's Hospital Seoul
Korea, Republic of Severance Hospital, Yonsei University College of Medicine Seoul
Mexico Hospital San Javier Guadalajara
Mexico Hospital General de Mexico Mexico City
Mexico Medica Sur Mexico City
Poland Wojskowy Szpital Kliniczny, Klinika Neurochirurgii Bydgoszcz
Poland Akademickie Centrum Kliniczne Gdansk
Poland SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii Lódz
Poland Samodzielny Publiczny Szpital Kliniczny nr 4, Klinika Neurochirurgii i Neurochirurgii Dzieciecej Lublin
Poland Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5 Sosnowiec
Poland Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie Warszawa
Russian Federation Chelyabinsk City Hospital #3; Department of Neurosurgery Chelyabinsk
Russian Federation State Institution Russian Oncology Research Center N.N. Blokhin Moscow
Russian Federation Samara Region Clinical Hospital M.I. Kalinin Samara
Russian Federation Military Medical Academy, Neurosurgery Dept St. Petersburg
Russian Federation Russian Scientific Research Neurosurgical Institute A.L. Polenov St. Petersburg
Spain Hospital de Cruces Baracaldo
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 Sevilla
Taiwan China Medical University Hospital Taichung
Taiwan Taichung Veterans General Hospital Taichung
Taiwan Tri-Service General Hospital Taipei City
United Kingdom Edinburgh Centre for Neuro-Oncology, Western General Hospital Edinburgh
United Kingdom The National Hospital for Neurology and Neurosurgery London
United States 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

Sponsors (1)

Lead Sponsor Collaborator
Isarna Therapeutics GmbH

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Brazil,  Canada,  France,  Germany,  Hungary,  India,  Korea, Republic of,  Mexico,  Poland,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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
Primary 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 Survival Rate at 12, 18, and 21 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 each time-point from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. 12, 18, and 21 months
Secondary Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants Survival status was assessed at each time-point from randomization. Participants with unknown or missing status were considered treatment failures, i.e., assumed to be dead. The category "Lost to follow-up" for each time-point includes participants who were alive at the last data collection point but did not yet have enough follow-up time to reach the time point. 12, 18, and 21 months
Secondary Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only) Median overall survival was defined as the date of randomization to the date of death. 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. Analysis was by Kaplan-Meier estimation. Up to 24 months
Secondary Response Category by Independent Review in the Intent-to-treat Population - Number of Participants Tumor response was classified based on the (neuro-)radiologist's evaluation according to the Macdonald Response Criteria for bidimensionally measurable disease as outlined below:
Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.
Partial Response (PR): =50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.
Progressive Disease (PD): =25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.
Stable Disease (SD): all other situations.
Two qualified neuro-radiologists reviewed scans at each MRI time point, with adjudication of discrepancies by a third reviewer. Their findings and clinical information were independently reviewed by a neuro-oncologist, who made the assessment of overall response.
Up to 24 months
Secondary Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only) Overall response rate was the proportion of participants with a best response of Complete Response (CR) or Partial Response (PR) observed from the start of treatment until disease progression. Up to 24 months
Secondary Tumor Control Rate (CR+PR+SD) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only) Tumor control rate was defined as the proportion of participants assessed as having Complete Response (CR), Partial Response (PR), or Stable Disease (SD). Participants with unknown or missing response were treated as non-responders. Up to 24 months
Secondary Median Duration of Response (Days) by Independent Review (Descriptive Analysis, Only) Duration of response was defined as the time from the first documentation of confirmed response (Complete Response, CR, or Partial Response, PR) to the first signs of Progressive Disease (PD), as assessed by the study neuro-oncologist. Median Duration of Response was calculated by Kaplan-Meier estimate.
Censoring rules were:
at the date of randomization -- participants without baseline assessments, or for those with no post-baseline timor assessments who were discontinued for other than progressive disease or death.
at the date of last tumor assessment -- discontinuation other than PD or death, or if a new treatment was started prior to disease progression
at the date of death or last tumor assessment -- death or PD after one missed tumor assessment
at the date of last tumor assessment -- death or PD after more than one missed tumor assessment
at the date of last tumor assessment -- participants on ongoing treatment at data cut-off
Up to 24 months
Secondary Disease Progression at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Number of Participants Tumor response was classified based on the (neuro-)radiologist's evaluation:
Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.
Partial Response (PR): =50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.
Progressive Disease (PD): =25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.
Stable Disease (SD): all other situations.
Based on clinical and imaging data, an independent neuro-oncologist made the final assessment of "Progressed" versus "Not Progressed". Participants who had MRI assessment results missing or unknown were "UNK or missing", and were treated as "Progressed" for the purposes of the calculation.
10, 12, 14, 16, 18, 21, and 24 months
Secondary 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) Tumor response was classified based on the (neuro-)radiologist's evaluation:
Complete Response (CR): Disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off steroids, neurologically stable or improved.
Partial Response (PR): =50% reduction in size of enhancing tumor on consecutive MRI scans at least 1 month apart, steroids stable or reduced, neurologically stable or improved.
Progressive Disease (PD): =25% increase in size of enhancing tumor or any new tumor on MRI scans, steroids stable or increased, neurologically worse.
Stable Disease (SD): all other situations.
Based on clinical and imaging data, an independent neuro-oncologist made the final assessment of "Progressed" versus "Not Progressed". Participants who had MRI assessment results missing or unknown were "UNK or missing", and were treated as "Progressed" for the purposes of the calculation.
10, 12, 14, 16, 18, 21 and 24 months
Secondary Median Time to Progression (Days) by Independent Review for the Intent-to-treat Population (Descriptive Analysis, Only) Time to progression was calculated from the date of randomization to the date of the first documented tumor progression. Participants who did not progress or died were censored at the last tumor assessment date or the date of start of a new anti-tumor treatment or death. Up to 24 months
See also
  Status Clinical Trial Phase
Recruiting NCT05664243 - A Phase 1b / 2 Drug Resistant Immunotherapy With Activated, Gene Modified Allogeneic or Autologous γδ T Cells (DeltEx) in Combination With Maintenance Temozolomide in Subjects With Recurrent or Newly Diagnosed Glioblastoma Phase 1/Phase 2
Completed NCT02768389 - Feasibility Trial of the Modified Atkins Diet and Bevacizumab for Recurrent Glioblastoma Early Phase 1
Recruiting NCT05635734 - Azeliragon and Chemoradiotherapy in Newly Diagnosed Glioblastoma Phase 1/Phase 2
Completed NCT03679754 - Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102 Phase 1
Completed NCT01250470 - Vaccine Therapy and Sargramostim in Treating Patients With Malignant Glioma Phase 1
Terminated NCT03927222 - Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma Phase 2
Recruiting NCT03897491 - PD L 506 for Stereotactic Interstitial Photodynamic Therapy of Newly Diagnosed Supratentorial IDH Wild-type Glioblastoma Phase 2
Active, not recruiting NCT03587038 - OKN-007 in Combination With Adjuvant Temozolomide Chemoradiotherapy for Newly Diagnosed Glioblastoma Phase 1
Completed NCT01922076 - Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas Phase 1
Recruiting NCT04391062 - Dose Finding for Intraoperative Photodynamic Therapy of Glioblastoma Phase 2
Active, not recruiting NCT03661723 - Pembrolizumab and Reirradiation in Bevacizumab Naïve and Bevacizumab Resistant Recurrent Glioblastoma Phase 2
Active, not recruiting NCT02655601 - Trial of Newly Diagnosed High Grade Glioma Treated With Concurrent Radiation Therapy, Temozolomide and BMX-001 Phase 2
Completed NCT02206230 - Trial of Hypofractionated Radiation Therapy for Glioblastoma Phase 2
Completed NCT03493932 - Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade Phase 1
Terminated NCT02709889 - Rovalpituzumab Tesirine in Delta-Like Protein 3-Expressing Advanced Solid Tumors Phase 1/Phase 2
Recruiting NCT06058988 - Trastuzumab Deruxtecan (T-DXd) for People With Brain Cancer Phase 2
Completed NCT03018288 - Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM) Phase 2
Not yet recruiting NCT04552977 - A Trail of Fluzoparil in Combination With Temozolomide in Patients With Recurrent Glioblastoma Phase 2
Withdrawn NCT03980249 - Anti-Cancer Effects of Carvedilol With Standard Treatment in Glioblastoma and Response of Peripheral Glioma Circulating Tumor Cells Early Phase 1
Withdrawn NCT02876003 - Efficacy and Safety of G-202 in PSMA-Positive Glioblastoma Phase 2