NEW AGENT FOR ANAPLASTIC ASTROCYTOMA

April 23, 2010 (Washington DC) — An investigational agent for high-grade gliomas has shown enough promise in the treatment of recurrent anaplastic astrocytoma in a phase 2 study that a phase 3 trial has been started.

The results of the phase 2 study were presented here at the American Association for Cancer Research (AACR) 101st Annual Meeting.

"There was a clear clinical benefit," said investigator Piotr Jachimczak, MD, during a meeting press conference about the new agent, trabedersen, in the treatment of anaplastic astrocytoma.

Dr. Jachimczak is a senior scientific advisor at Antisense Pharma (Regensburg, Germany), the developer of the drug.

Trabedersen is a phosphorothioate antisense oligonucleotide and a TGF-beta 2 inhibitor.

"Almost all high-grade gliomas express TGF-beta 2," he said via phone at the press conference. Dr. Jachimczak was unable to attend the AACR meeting because of air travel restrictions in Europe related to the volcano eruption in Iceland.

In the study, 145 patients with recurrent or refractory high-grade glioma (glioblastoma or anaplastic astrocytoma) were randomly assigned to receive either trabedersen (10 or 80 μmol/L) or standard chemotherapy. Patients receiving standard chemotherapy, which was the control group, were treated with either temozolomide or vincristine.

Overall, trabedersen 10 μmol/L was superior to trabedersen 80 μmol/L in both efficacy and safety for high-grade gliomas, the investigators report.

However, the lower dose of trabedersen was most effective in patients with anaplastic astrocytoma, reported Dr. Jachimczak.

In patients with anaplastic astrocytoma, the trabedersen 10 μmol/L group (n = 12) had a higher overall survival rate at 24 months than the trabedersen 80 μmol/L group (n = 15) and the control group (n = 12) (83.3%, 53.3% and 41.7%, respectively).

Dr. Jachimczak and colleagues reported that the duration of response for patients with anaplastic astrocytoma was about 3 times longer in the 10 μmol/L group (29.1 months) than in the control group (8.0 months).

They also reported that the median overall survival for patients with anaplastic astrocytoma was higher in both trabedersen groups than in the chemotherapy control group, with "a remarkable survival benefit" for 10 μmol/L trabedersen over chemotherapy (17.4 months).

Not as Effective in Glioblastomas

Trabedersen was not as impressive in the treatment of glioblastomas.

In glioblastoma patients, trabedersen was only as effective as standard chemotherapy.

However, there was a subset of patients in whom the agent was more effective. In patients younger than 55 years with glioblastoma, the 2-year survival rate was 44%, compared with 13.3% with standard chemotherapy.

Overall, the study results suggest that trabedersen could be a boon to patients with anaplastic astrocytoma, suggested Dr. Jachimczak.

"Current therapies for this patient population include surgery, radiation, and chemotherapy with temozolomide," said Dr. Jachimczak in a press statement. "Trabedersen performed better than these therapy standards on all levels in anaplastic astrocytoma."

Also of note is the fact that trabedersen is administrated intratumorally, using convection-enhanced delivery. "It allows avoidance of a surgical procedure," said Dr. Jachimczak.

In the study, trabedersen was given for up to 11 treatment cycles (7 days on, 7 days off).

Expert Offers Comment

Despite the positive results in the trial, a glioma expert approached for comment by Medscape Oncology found the study abstract presented at AACR to be a bit puzzling.

"In this abstract, no information is given on the toxicity experienced by the patients or the reason, or at least a hypothesis, why the 10 μmol/L was more effective than the 80 μmol/L dose," said Annick Desjardins, MD, assistant professor of medicine at the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center in Durham, North Carolina.

Dr. Desjardins also noted that the 24-month survival data were out of the ordinary.

"When recurrent malignant glioma studies are published, the results are published using 6-month and median progression-free survival, and 6- or 12-month overall and median survival. In this abstract, they use a survival rate and duration of response at 24 months, so it's difficult to compare the results with previously published trials," she said.

Dr. Desjardins provided some perspective about the study results for recurrent anaplastic astrocytoma.

"At the time of disease progression, additional interventions for anaplastic astrocytomas have demonstrated a median progression-free survival anywhere from 3 to 13 months (majority around 6 months), with a median overall survival around 14 to 15 months."

Dr. Desjardins had reservations about the control groups in the study.

"The control groups used are not optimal," she said.

She explained that "temozolomide is now the standard of care for malignant gliomas, including anaplastic astrocytomas and, thus, all the patients treated with trabedersen most probably presented disease progression/recurrence while receiving treatment with temozolomide."

Furthermore, she said that, for major brain tumor centers, "[vincristine] is not part of the first treatment choice at the time of disease progression because of the severe hematologic toxicities experienced by the patients on this regimen."

A randomized multinational and active-controlled phase 3 study of trabedersen has begun. The trial is known as SAPPHIRE (Efficacy and Safety of AP 12009 in Adult Patients With Recurrent or Refractory Anaplastic Astrocytoma [WHO Grade 3] as Compared to Standard Treatment with Temozolomide or BCNU: A Randomized, Actively Controlled, Open label Clinical Phase 3 Study).

In SAPPHIRE, patients are randomized to treatment with either 10 μmol/L trabedersen or standard chemotherapy (temozolomide or BCNU).

Dr. Desjardins reports serving as a speaker for UCB Pharma for their seizure medicines.

American Association for Cancer Research (AACR) 101st Annual Meeting: Abstract 3716. Presented April 20, 2010.