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R115777 May Be Effective Against Certain Subtypes of Recurrent Glioblastoma Multiforme

R115777 May Be Effective Against Certain Subtypes of Recurrent Glioblastoma Multiforme

LOS ANGELES—The North American Brain Tumor Consortium (NABTC) reported
that R115777 (Zarnesta) shows modest activity against recurrent glioblastoma
multiforme and might be effective as a therapy for certain subtypes of these
aggressive brain tumors (ASCO abstract 317).

The phase II study involved 42 glioma patients, 33 with glioblastoma
multiforme. Five of those 33 responded to R115777, according to lead
investigator Timothy Cloughesy, MD, director of the Neuro-Oncology Program
at the University of California, Los Angeles. Three had partial responses,
and two had stable disease. Four are without progression for greater than 15
months, he said, describing the response as durable. The fifth died of
pneumonia believed to be unrelated to the treatment. Median time to
progression with R115777 was no better than current therapies, 8 weeks.

"There seems to be a subpopulation that responds," Dr.
Cloughesy said, describing the results as encouraging but not specific
enough to predict who would benefit. "One of the goals is to define the
subpopulation that responds," he said. "Investigators are
attempting to identify this group. There are many leads but no clear answer
yet."

Dr. Cloughesy and his colleagues concluded that R115777 is tolerable in
the patient population that has been tested, when delivered orally at 300 mg
bid in repeating 28-day cycles of 21 days on-drug and 7 days off-drug.
Toxicity forced three patients to go off trial. Grade 3/4 adverse events
included three cases of granulocytopenia and one each of depressed
consciousness, constipation, leukopenia, photophobia, skin rash, and
thrombocytopenia.

Second Phase II Trial

An experimental molecular therapy, R115777 inhibits farnesyl transferase,
an enzyme that activates a number of proteins, including the Ras oncogene.
R115777 has shown activity against leukemia and breast cancer, and the NABTC
plans to study R115777 in combination with external beam radiation for
glioblastoma multiforme.

But first, a second phase II trial of R115777 in recurrent glioblastoma
multiforme is planned, with patients taking enzyme-inducing anti-epileptic
drugs (EIAEDs) for protection against seizures. None of the patients in the
previous phase II trial were taking EIAEDs, although the drugs are commonly
given to patients with brain tumors.

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