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ASCO: Pipeline Drug Said to Shrink Recurrent Brain Tumors
By Peggy Peck, Senior Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
May 18, 2005
Also covered by: ABC News
ORLANDO, May 18-An investigational anti-angiogenesis drug called enzastaurin, or LY317615, has led to tumor shrinkage in 22% of patients with recurrent glioblastoma, a heavily vascularized cancer.
Preliminary results from a phase II trial showed CT- or MRI-confirmed tumor shrinkage after more than 18 weeks of daily treatment with enzastaurin for 22% of patients with recurrent glioblastoma multiforme (GBM) and 25% of patients with recurrent anaplastic glioma (AG).
Moreover, 5% of GBM (MAX) patients had stable disease as did 13% of AG patients, said Howard Fine, M.D., chief of neuro-oncology at the National Cancer Institute, who reported the findings Tuesday at the American Society of Clinical Oncology meeting here.
"The drug looks promising, but the numbers are small so it is too soon to get excited," Dr. Fine said in an interview. "But I am optimistic about this drug because it is very difficult to show any activity in patients with recurrent glioblastoma. This is a very tough disease."
In general, glioblastomas respond to initial treatment but then recur and become lethal. Since glioblastoma is a heavily vascularized cancer, it is an excellent target for an anti-angiogenic agent, Dr. Fine said.
Enzastaurin is a macrocyclic bisindolymaleimide that demonstrated significant anti-angiogenic effect as well as direct antiglioma activity in vitro. And in this clinical study, "it appears that the drug not only shrinks the tumor by attacking its blood supply but also by killing cancer cells directly," Dr. Fine said.
The study recruited 92 patients with recurrent disease who had a history of failed chemotherapy and radiation therapy. Fifty-five of the patients were men.
Seventy-six patients not taking enzyme inducing anti-epileptic drugs such as Neurontin (gabapentin) and Lamictal (levetiracetam) were randomized to 500 mg enzastaurin daily. Arm B of the study included 16 patients taking enzyme inducing anti-epileptic drugs such as Tegretol (carbamazepine) or phenobarbital. They were randomized to escalating therapy: of 525 mg, 700 mg, and 900 mg.
Response was defined as objective radiographic response or stable disease for more than three months.
"We stopped accruing patients to arm B when we were unable to demonstrate pharmacokinetic response at 900 mg," he said.
Among the findings:
Eight-seven patients (63 GBMs and 24 AGs) were evaluable for response.
The overall radiographic response rate was 23% (20/87 patients) and the overall stable response rate was 7% (6/87 patients).
Fourteen of 63 GBM patients had an objective response (22%) and three patients had stable disease (5%).
Six of 24 AG patients had objective response and three of 24 had stable disease, for response rates of 25% and 13% respectively.
The overall progression free survival for both responders and patients with stable disease is about five months.
Thrombocytopenia was reported in 16% of patients and 3% of those patients had grade 3 or 4 toxicity.
Dr. Fine said the experience with escalating doses in arm B of the study suggest that "we have not determined the maximal tolerated dose nor have we determined whether it is possible to attain higher exposure levels." For that reason the next step, he said, will be a pharmacological-driven phase I trial to answer those questions.
Eli Lilly and Company, which is developing the drug, announced that it is planning a phase III trial comparing enzastaurin to temozolomide and radiation for treatment of recurrent glioblastoma.