In this multinational Phase III study the efficacy and safety of 10 µM AP 12009 is compared to standard chemotherapy (temozolomide or BCNU) in adult patients with confirmed recurrent or refractory anaplastic astrocytoma (WHO grade III).

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) in adult patients with recurrent or refractory anaplastic astrocytoma (AA, WHO grade III). 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.

• Drug: trabedersen
  10 µM AP 12009 (trabedersen), intratumoral infusion, every other week, 11 cycles, maximum 21 weeks
• Drug: temozolomide or carmustine for infusion
  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
  Other Names:

  • Temodar
  • Temodal
  • TMZ
  • BCNU
  • BiCNU
  • Carmubris
• Device: Drug delivery system for administration of AP 12009
  Drug delivery system for Convection Enhanced Delivery consists of a portable pump with drug reservoir and infusion line. Main implanted parts are the port access system and the intratumoral 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.

• AP 12009 10 µM: Experimental
  Interventions:

  • Drug: trabedersen
  • Device: Drug delivery system for administration of AP 12009
  • Procedure: Placement of Drug Delivery System
• Chemotherapy: Active Comparator
  Intervention: Drug: temozolomide or carmustine for infusion

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 diagnosis of AA (WHO grade III) as confirmed by central histopathology.
• The patient has a measurable lesion (> 2 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).
• The patient has recurrent or refractory disease.
• 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 patient is amenable to surgical resection of the tumor.
• Tumor surgery, tumor debulking, or other neurosurgery within 30 days prior to randomization.
• Radiotherapy or stereotactic (gamma knife) radiosurgery within 3 months prior to randomization.
• Prior interstitial brachytherapy.
• 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 defined as significant impression of the ventricular system and/ or a midline shift (≥3 mm, central MRI review).
• Participation in another clinical trial 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.
• Lung function: vital capacity ≤ 70%.
• History of allergies to reagents used in this study.
• Drug abuse or extensive use of alcohol.
• Clinically relevant psychiatric disorders / legal incapacity or a limited legal capacity.