APG101 in Glioblastoma

• Safety and tolerability of APG101 [ Time Frame: ongoing during study ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: until progression of underlying disease ] [ Designated as safety issue: No ]
• Objective response rates (OR) [ Time Frame: ongoing during study ] [ Designated as safety issue: No ]
• Duration of response (DR) in responders [ Time Frame: ongoing during study ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: until study and after end of study (by 8-weekly phone calls) ] [ Designated as safety issue: No ]
• Quality of life [ Time Frame: ongoing during study ] [ Designated as safety issue: No ]
• Cognitive function [ Time Frame: ongoing during study ] [ Designated as safety issue: No ]

• Safety and tolerability of APG101 [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Objective response rates (OR) [ Designated as safety issue: No ]
• Duration of response (DR) in responders [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Quality of life [ Designated as safety issue: No ]
• Cognitive function [ Designated as safety issue: No ]

This is a phase II study of APG101 + reirradiation (RT) versus reirradiation. Patients suffering from a malignant brain tumor called glioblastoma having a first or second progression can be included. They will be randomized to RT or RT + APG101.

APG101 is a fusion protein (similar to an antibody) and will be administered as a weekly infusion. Patients can stay in this study as long as they benefit from the participation (no fixed end).

In this trial, 30-35 sites in Germany, Austria and Russia take part.

In this phase II trial, patients with a recurrence / progression of glioblastoma (first or second progression) either not being eligible for tumour resection or having macroscopic residual tumour after resection of the recurrence can be included (tumor size must 1-4 cm in T1-weighted MRI). They must be candidates for a re-irradiation and will then be randomized in a 1:2 ratio to re-irradiation alone or re-irradiation + 400mg APG101 as a weekly intravenous infusion.

Radiotherapy (RT) is considered standard of care and not a study procedure. As prior therapies, a first radiotherapy (maximal dose of 60 Gy; at least 8 months since the end of preirradiation), a prior surgery (at least for histology) and at least one Temozolomide-containing chemotherapy are mandatory; patients with prior treatment with bevacizumab, iodine seeds and/or brachytherapy are not eligible. The patients' steroid dose must be stable or decreasing upon inclusion.

The number of patients to be included in this study is up to 83 (depending on the statistical 2-step SIMON design).

Primary objective: 6 months rate of progression free survival (PFS6). Subjects can participate in this study as long as a clinical benefit is considered by the treating physician.

MRI tumour imaging will be carried out every 6 weeks.

• Drug: APG101
  400mg weekly as intravenous infusion
  Other Name: Recombinant fusion protein
• Procedure: Blood drawing
  Blood drawings, e.g. for safety labs, abdominal ultrasound, ECG. Re-Irradiation is not considered a study procedure, but standard of care (inclusion criterion)
  Other Name: n.a.

• Active Comparator: Re-Irradiation
  33% of the patients will be randomized to reirradiation (RT) alone. They will receive 36 Gy (2 Gy per fraction)
  Intervention: Procedure: Blood drawing
• Experimental: Re-Irradiation + APG101
  66% of the patients will be randomized to reirradiation (RT) + 400 mg APG101 weekly. They will receive 36 Gy (2 Gy per fraction) and 400 mg APG101 weekly as an intravenous infusion
  Intervention: Drug: APG101

Inclusion Criteria:

• Male and female patients with a recurrence / progression of glioblastoma either not being eligible for tumour resection or having macroscopic residual tumour after resection of the recurrence
• Diagnosis of glioblastoma must be proven histologically and progress must be documented by MRI. MRI images must not be older than 2 weeks before first dosing/start of RT
• Not more than two prior therapy regimens including one or two resections, one or two chemotherapies of which one must have been TMZ-containing and one radiotherapy (RT) for the brain tumour
• Previous irradiation therapy of the primary tumour with a maximal dose of 60 Gy; at least 8 months since the end of preirradiation
• Candidate for reirradiation with recurrent tumour visible on MRI-T1 (Gd) and with the largest diameter measuring 1 cm to 4 cm
• Informed consent
• Age at least 18 years, smoking or non-smoking, of any ethnic origin
• Karnofsky performance index (KPI) ≥ 60%
• Neutrophile counts > 1500/μl / Platelet counts > 80.000/μl / Haemoglobin > 10 g/dl / Serum creatinine < 1.5-fold upper normal range / Bilirubin, AST or ALT < 2,5-fold upper normal range unless attributed to anticonvulsants / Alkaline phosphatase < 2,5-fold upper normal range
• Adequate contraception
• Stable or decreasing treatment with steroids within 5 days before treatment start

Exclusion Criteria:

• More than one RT of brain, prior first radiotherapy with more than 60 Gy
• Cumulative total dose on the optical chiasm >54 Gy for 2 Gy/fraction, α/β=2
• Prior treatment with bevacizumab, iodine seeds and/or brachytherapy
• Unable to undergo MRI
• Past medical history of diseases with poor prognosis according to the judgement of the Investigator, e.g. severe coronary heart disease, severe diabetes, immune deficiency, residual deficits after stroke, severe mental retardation
• HIV or hepatitis infection
• Pregnancy or breast feeding
• Treatment within any other clinical trial parallel to the treatment phase of the current study or within 30 days before inclusion
• Known active coronary artery disease, significant cardiac arrhythmias or severe congestive heart failure (NYHA class III - IV)