Efficacy and Safety of AP 12009 in Adult Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma as Compared to Standard Chemotherapy Treatment: A Randomized, Actively Controlled, Open Label Clinical Phase III Study.
- The patient has provided written informed consent prior to any study-related
- 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
- 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
- The patient is male or a non-pregnant, non-lactating female.
- Females of childbearing potential must have a negative beta-HCG pregnancy test at
- 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
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)
- 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
- Prior interstitial brachytherapy of the brain with permanent implants. Prior
interstitial brachytherapy of the brain with removable implants within 3 months prior
- 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
- 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
- Concomitant treatment with yellow fever vaccine.