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

Phase 3

Terminated

Conditions: Anaplastic Astrocytoma
Glioblastoma

Interventions: Drug: temozolomide
Drug: trabedersen
Drug: carmustine
Device: Drug delivery system for administration of AP 12009
Procedure: Placement of Drug Delivery System
Drug: lomustine

Registration Number: NCT00761280

Lead Sponsor: Isarna Therapeutics GmbH

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 27

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

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
trabedersen 10 µM	Placement of Drug Delivery System	10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Chemotherapy	carmustine	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.
trabedersen 10 µM	Drug delivery system for administration of AP 12009	10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Chemotherapy	temozolomide	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.
Chemotherapy	lomustine	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.
trabedersen 10 µM	trabedersen	10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks

Primary Outcome Measures

Name	Time	Method
Survival Rate at 24 Months in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	24 months	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.
Survival at 24 Months in the Intent-to-treat Population - Number of Participants	24 months	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.

Secondary Outcome Measures

Name	Time	Method
Median Overall Survival (Days) From Randomization in the Intent-to-treat Population (Descriptive Analysis, Only)	Up to 24 months	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.
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 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.
Survival at 12, 18, and 21 Months in the Intent-to-treat Population - Number of Participants	12, 18, and 21 months	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.
Overall Response Rate (CR+PR) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Up to 24 months	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.
Response Category by Independent Review in the Intent-to-treat Population - Number of Participants	Up to 24 months	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.
Median Time to Progression (Days) by Independent Review for the Intent-to-treat Population (Descriptive Analysis, Only)	Up to 24 months	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.
Median Duration of Response (Days) by Independent Review (Descriptive Analysis, Only)	Up to 24 months	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
Tumor Control Rate (CR+PR+SD) by Independent Review in the Intent-to-treat Population - Percentage of Participants (Descriptive Analysis, Only)	Up to 24 months	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.
Disease Progression at 10, 12, 14, 16, 18, 21, and 24 Months by Independent Review in the Intent-to-treat Population - Number of Participants	10, 12, 14, 16, 18, 21, and 24 months	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.
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)	10, 12, 14, 16, 18, 21 and 24 months	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.

Trial Locations

Locations (67): FLENI
🇦🇷
Ciudad Autónoma de Buenos Aires, Argentina
NJ Neuroscience Institute; JFK Medical Center
🇺🇸
Edison, New Jersey, United States
University of Rochester Medical Center
🇺🇸
Rochester, New York, United States
Hospital Británico
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Ciudad Autónoma de Buenos Aires, Argentina
Sanatorio Allende
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Córdoba, Argentina
Universitätsklinik Innsbruck, Abteilung für Neurologie
🇦🇹
Innsbruck, Austria
AKH Wien, Klinik für Neurochirurgie
🇦🇹
Wien, Austria
ECOGENE-21 Centre d'études cliniques
🇨🇦
Chicoutimi, Quebec, Canada
Postgraduate Institute of Medical Education & Research (PGIMER)
🇮🇳
Chandigarh, India
Apollo Speciality Hospitals
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Chennai, India
Manipal Hospital & Manipal Institute for Neurological Disorders
🇮🇳
Bangalore, India
NIMHANS
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Bangalore, India
BGS Global Hospital
🇮🇳
Bangalore, India
Amrita Institute of Medical Sciences Research Center
🇮🇳
Cochin, India
Care Hospitals
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Hyderabaad, India
AMRI Hospitals
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Kolkata, India
SGPGI of Medical Sciences
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Lucknow, India
Hospital San Javier
🇲🇽
Guadalajara, Mexico
Advanced Centre for Treatment Research and Education in Cancer (ACTREC)
🇮🇳
Mumbai, India
All India Institute of Medical Sciences (AIIMS)
🇮🇳
New Delhi, India
Hospital General de Mexico
🇲🇽
Mexico City, Mexico
Wojskowy Szpital Kliniczny, Klinika Neurochirurgii
🇵🇱
Bydgoszcz, Poland
Centrum Onkologii - Instytut Im. Marii Sklodowskiej-Curie
🇵🇱
Warszawa, Poland
Akademickie Centrum Kliniczne
🇵🇱
Gdańsk, Poland
Samodzielny Publiczny Szpital Kliniczny nr 4, Klinika Neurochirurgii i Neurochirurgii Dziecięcej
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Lublin, Poland
Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5
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Sosnowiec, Poland
SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii
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Łódź, Poland
State Institution Russian Oncology Research Center N.N. Blokhin
🇷🇺
Moscow, Russian Federation
Samara Region Clinical Hospital M.I. Kalinin
🇷🇺
Samara, Russian Federation
China Medical University Hospital
🇨🇳
Taichung, Taiwan
Tri-Service General Hospital
🇨🇳
Taipei City, Taiwan
Taichung Veterans General Hospital
🇨🇳
Taichung, Taiwan
Foothills Medical Centre
🇨🇦
Calgary, Canada
Hospital de Clínicas de Porto Alegre
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Porto Alegre, Brazil
Klinik und Poliklinik für Neurologie
🇩🇪
Regensburg, Germany
Centro Goiano de Oncologia (CGO)
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Goiania, Brazil
Hospital Sao Vicente de Paulo
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Passo Fundo, Brazil
Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg
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Günzburg, Germany
Klinik und Poliklinik für Neurochirurgie
🇩🇪
Münster, Germany
Edinburgh Centre for Neuro-Oncology, Western General Hospital
🇬🇧
Edinburgh, United Kingdom
Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
🇭🇺
Szeged, Hungary
SCTIMST, Dept. of Neurosurgery
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Thiruvananthapuram, India
Hospital de Câncer de Barretos
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Barretos / SP, Brazil
Medizinische Hochschule Hannover Neurochirurgische Klinik
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Hannover, Germany
Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie
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Hamburg, Germany
Hospital Sao Lucas da PUCRS
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Porto Alegre, Brazil
Kangnam St. Mary's Hospital
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Seoul, Korea, Republic of
Montreal Neurological Institute and Hospital
🇨🇦
Montreal, Canada
Hospital do Servidor Público Estadual
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Sao Paulo, Brazil
Severance Hospital, Yonsei University College of Medicine
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Seoul, Korea, Republic of
Universitätsklinikum Freiburg
🇩🇪
Freiburg, Germany
The National Hospital for Neurology and Neurosurgery
🇬🇧
London, United Kingdom
Hospital Universitario Virgen del Rocío
🇪🇸
Sevilla, Spain
Hospital Doce de Octubre
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Madrid, Spain
Hospital de Cruces
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Baracaldo, Spain
Asan Medical Center
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Seoul, Korea, Republic of
Medica Sur
🇲🇽
Mexico City, Mexico
Russian Scientific Research Neurosurgical Institute A.L. Polenov
🇷🇺
St. Petersburg, Russian Federation
Hospital Universitario Marqués de Valdecilla
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Santander, Spain
Hospital Universitario Vall d'Hebron
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Barcelona, Spain
Winthrop University Hospital
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Mineola, New York, United States
Universitätsklinikum Leipzig, Neurochirurgische Klinik
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Leipzig, Germany
La Timone University Hospital
🇫🇷
Marseille, France
Universitätsklinik Heidelberg Neurologische Klinik
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Heidelberg, Germany
Otto-von-Guericke-Universität, Klinik für Neurochirurgie
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Magdeburg, Germany
Chelyabinsk City Hospital #3; Department of Neurosurgery
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Chelyabinsk, Russian Federation
Military Medical Academy, Neurosurgery Dept
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St. Petersburg, Russian Federation