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

Inclusion Criteria:

• The patient has provided written informed consent prior to any study-relatedprocedure.

• 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 afterprior surgery and radiotherapy at any time of the disease course or stage. SecondaryGBM patients have progressed after a previous diagnosis of A and/or AA.

• The patient has not received more than one chemotherapy regimen. Radiation withconcomitant chemotherapy, followed by adjuvant chemotherapy, is considered as onechemotherapy regimen.

• The patient is eligible for chemotherapy.

• The patient is on a maximum dose of 4 mg/day dexamethasone or equivalent doses forother corticosteroids, which has been stable or decreasing for at least 3 weeks priorto Screening.

• The patient is male or a non-pregnant, non-lactating female.

• Females of childbearing potential must have a negative beta-HCG pregnancy test atScreening.

• 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 screeninglaboratory values:

1. Adequate renal function determined by serum creatinine and urea < 2 times theupper 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 torandomization. If a ≤48-hour routine post-surgery MRI (in accordance with studyspecifications) qualifies the patient for study participation, the patient can berandomized 30 ± 7 days post-surgery.

• Radiotherapy or stereotactic (gamma knife) radiosurgery within 3 months prior torandomization.

• Prior interstitial brachytherapy of the brain with permanent implants. Priorinterstitial brachytherapy of the brain with removable implants within 3 months priorto randomization.

• Chemotherapy, hormone therapy, or any other therapy with established or suggestedanti-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 significantcompression of the ventricular system and/or a midline shift (≥ 3 mm, central MRIreview). Compression of the ventricular system and/or a midline shift ≥ 3 mm only dueto the presence of (a) cyst(s) or scarring processes does not exclude an individualfrom the study.

• Participation in another clinical study with another investigational medicinal productwithin 30 days prior to randomization.

• History of a second independent malignant disorder within 5 years, except forcarcinoma 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. Myocardialinfarction 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 anyconditions, 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 causelung 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 legalcapacity.

• Concomitant treatment with yellow fever vaccine.