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

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 oligodeoxynu...

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)
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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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
trabedersen 10 µMPlacement of Drug Delivery System10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Chemotherapycarmustinetemozolomide: 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 µMDrug delivery system for administration of AP 1200910 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Chemotherapytemozolomidetemozolomide: 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.
Chemotherapylomustinetemozolomide: 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 µMtrabedersen10 µM trabedersen (AP 12009), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
Primary Outcome Measures
NameTimeMethod
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 Participants24 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
NameTimeMethod
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 Participants12, 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 p...

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 ParticipantsUp 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.
...

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:
...

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 Participants10, 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.
...

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.
...

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

🇦🇷

Ciudad Autónoma de Buenos Aires, Argentina

Sanatorio Allende

🇦🇷

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

🇮🇳

Chennai, India

Manipal Hospital & Manipal Institute for Neurological Disorders

🇮🇳

Bangalore, India

NIMHANS

🇮🇳

Bangalore, India

BGS Global Hospital

🇮🇳

Bangalore, India

Amrita Institute of Medical Sciences Research Center

🇮🇳

Cochin, India

Care Hospitals

🇮🇳

Hyderabaad, India

AMRI Hospitals

🇮🇳

Kolkata, India

SGPGI of Medical Sciences

🇮🇳

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

🇵🇱

Lublin, Poland

Kliniczny Oddzial Neurochirurgii SUM w Sosnowcu Wojewódzki Szpital Specjalistyczny nr 5

🇵🇱

Sosnowiec, Poland

SP ZOZ Uniwersytecki Szpital Kliniczny nr 1, Klinika Neurochirurgii

🇵🇱

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

🇧🇷

Porto Alegre, Brazil

Klinik und Poliklinik für Neurologie

🇩🇪

Regensburg, Germany

Centro Goiano de Oncologia (CGO)

🇧🇷

Goiania, Brazil

Hospital Sao Vicente de Paulo

🇧🇷

Passo Fundo, Brazil

Neurochirurgische Klinik an der Universität Ulm am Bezirkskrankenhaus Günzburg

🇩🇪

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

🇮🇳

Thiruvananthapuram, India

Hospital de Câncer de Barretos

🇧🇷

Barretos / SP, Brazil

Medizinische Hochschule Hannover Neurochirurgische Klinik

🇩🇪

Hannover, Germany

Universitätklinikum Hamburg-Eppendorf, Klinik für Neurochirurgie

🇩🇪

Hamburg, Germany

Hospital Sao Lucas da PUCRS

🇧🇷

Porto Alegre, Brazil

Kangnam St. Mary's Hospital

🇰🇷

Seoul, Korea, Republic of

Montreal Neurological Institute and Hospital

🇨🇦

Montreal, Canada

Hospital do Servidor Público Estadual

🇧🇷

Sao Paulo, Brazil

Severance Hospital, Yonsei University College of Medicine

🇰🇷

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

🇪🇸

Madrid, Spain

Hospital de Cruces

🇪🇸

Baracaldo, Spain

Asan Medical Center

🇰🇷

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

🇪🇸

Santander, Spain

Hospital Universitario Vall d'Hebron

🇪🇸

Barcelona, Spain

Winthrop University Hospital

🇺🇸

Mineola, New York, United States

Universitätsklinikum Leipzig, Neurochirurgische Klinik

🇩🇪

Leipzig, Germany

La Timone University Hospital

🇫🇷

Marseille, France

Universitätsklinik Heidelberg Neurologische Klinik

🇩🇪

Heidelberg, Germany

Otto-von-Guericke-Universität, Klinik für Neurochirurgie

🇩🇪

Magdeburg, Germany

Chelyabinsk City Hospital #3; Department of Neurosurgery

🇷🇺

Chelyabinsk, Russian Federation

Military Medical Academy, Neurosurgery Dept

🇷🇺

St. Petersburg, Russian Federation

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