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