Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma
Condition: Anaplastic Astrocytoma; Glioblastoma
MeSH terms: Glioblastoma; Astrocytoma
Intervention: trabedersen; temozolomide; Drug delivery system for administration of AP 12009; Placement of Drug Delivery System; carmustine; lomustine
Intervention description: Drug delivery system for Convection Enhanced Delivery consists of a portable pump (Pegasus vario or Pega vario) with drug reservoir (Pega Bag) and infusion line (Pega Line). Main implanted parts are the port access system (PORT-A-CATH) and the intratumoral catheter (Medtronic ventricular catheter).; Surgery for placement of intratumoral catheter and subcutaneous port access system as per routine clinical practice. Stereotactical catheter placement controlled by CT.
Intervention MeSH terms: Temozolomide; Carmustine; Lomustine; Trabedersen
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 27.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Anaplastic astrocytoma; Glioblastoma; Antisense; Cancer; Transforming Growth Factor beta 2; Targeted therapy; Brain tumor; Glioma; Central Nervous System (CNS); Convection Enhanced Delivery (CED); Intratumoral administration

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).
    

Eligibility criteria:

        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.