Completed studies

Phase I/II studies

Three Phase I/II clinical studies have been completed, in which the safety and tolerability of trabedersen (AP 12009) was evaluated in humans. These studies were designed to determine the maximum tolerated dose of trabedersen in adult patients with recurrent or refractory high-grade glioma, anaplastic astrocytoma (WHO grade III) or glioblastoma (WHO grade IV). Even after the dose of trabedersen had been increased by more than 100-fold, an independent committee of experts rated the therapy as being safe. The drug was well tolerated by the patients who participated in these studies.

Preliminary data on the efficacy of trabedersen was also obtained in these studies. For several patients, magnetic resonance imaging (MRI) and clinical findings showed stabilization of the disease, and in two patients, there was complete and long-lasting regression of the tumor. One of these patients (diagnosed with recurrent anaplastic astrocytoma) is still alive, more than 6 years after receiving treatment with trabedersen. These are remarkable outcomes considering the poor prognosis of these patients.

Phase IIb study

The objective of the multinational Phase IIb study was to determine the efficacy and safety of trabedersen (AP 12009) in patients with recurrent or refractory high-grade glioma. In total, 145 patients with recurrent or refractory anaplastic astrocytoma (WHO grade III) or with recurrent or refractory glioblastoma (WHO grade IV) were randomly assigned to receive either trabedersen (10μM or 80μM dose) or standard chemotherapy with either temozolomide or PCV. The results of the study showed that trabedersen was well tolerated. Long-lasting tumor responses (either stabilization of tumor growth or tumor regression) were observed in a number of patients with anaplastic astrocytoma or glioblastoma. In a number of patients, tumor response continued long-term after the end of the treatment with trabedersen.

The major results from the Phase IIb study in patients with recurrent or refractory anaplastic astrocytoma were as follows:

• The current median survival time for patients treated with 10μM trabedersen is 39.1 months compared with 21.7 months in the chemotherapy control arm. The survival benefit with 10μM trabedersen is, therefore, 17.4 months vs. chemotherapy (data as of August 2008).
• 83% of patients treated with 10μM trabedersen survived for at least 2 years, compared with 42% of patients treated with standard chemotherapy.
• In patients treated with 10μM trabedersen, the overall tumor response rate steadily increased, and 42% of patients had a partial or complete tumor response after 14 months. During the same period, the overall response rate in the chemotherapy control group fell to zero, from a peak of 25% after 6 months.

The 10μM concentration of trabedersen is the recommended dose for the future clinical development in high-grade glioma patients.

The clinical findings from the Phase IIb study are now being further investigated in patients with recurrent or refractory anaplastic astrocytoma in the Phase III SAPPHIRE study.