Trabedersen, a novel TGF-beta 2 inhibitor, performed well when compared with standard chemotherapy for high-grade gliomas in a phase IIb trial that enrolled 145 patients with recurrent or refractory stage III or IV disease.
Patients with anaplastic astrocytomas had the best results, Dr. Piotr Jachimczak said in a telephone call from Germany to a press briefing at the meeting in Washington, where the data were presented.
Younger patients with glioblastoma also fared better than controls treated with temozolomide or vincristine, said Dr. Jachimczak, senior scientific adviser at Antisense Pharma, the drug's developer, in Regensburg. Other study investigators also are employees of the company.
Trabedersen has orphan drug status in the United States and Europe for glioma, a brain tumor that often overexpresses TGF-beta 2. A phosphorothioate antisense oligonucleotide, the drug is administered intra-tumorally via convection-enhanced delivery. This enables trabedersen to cross the blood-brain barrier, Dr. Jachimczak said.
Patients in the study received trabedersen in 10 mcM or 80 mcM doses 7 days on and 7 days off, for up to 11 cycles or standard therapy. The investigators reported the lower dose of trabedersen was “superior in efficacy and safety.”
Among patients with anaplastic astrocytomas, the survival rate at 24 months was 83.3% with the low dose, 53.3% with the high dose, and 41.7% with standard therapy. Responses lasted about 3 times longer in the low-dose cohort than in the standard chemotherapy group: 29.1 months vs. 8.0 months. Both trabedersen groups had better median overall survival than the control group, with the benefit in the low-dose group reported as a gain of 17.4 months.
The overall benefit in glioblastoma patients was described as being “as efficacious as standard chemotherapy.” In a prespecified subgroup of patients who were less than 55 years of age and had Karnofsky performance scores of less than 80%; however, trabedersen-treated patients had a 2-year survival rate of 40% vs. 13.3% with standard chemotherapy.
Investigators are enrolling glioma patients for a randomized, multinational phase III trial of trabedersen called the SAPPHIRE study.
My Take
Astrocytoma Results Are 'Encouraging'
Previous attempts to cross the blood-brain barrier by infusing therapeutic agents into the tumor and the surrounding brain using convection enhanced delivery have been largely unsuccessful. However, this study with trabedersen, administered by convection-enhanced delivery, suggests that this approach may have promise. Repeated administration was feasible and appeared to be safe. Trabedersen had only modest activity in patients with glioblastomas but the results with anaplastic astrocytomas (AAs) were encouraging. The significant increase in survival for patients with AA treated with trabedersen, compared with standard chemotherapy, is striking. Nonetheless, the results must be interpreted with caution because of the small numbers of patients in each group (less than 20), and the possibility of selection bias.
PATRICK Y. WEN, M.D., is director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women's Cancer Center, Boston.
