NEW YORKAn antisense drug that targets a protein that
interferes with the actions of chemotherapeutic agents is entering phase III
trials, said Raymond P. Warrell, Jr., MD, president and chief executive
officer, Genta Inc., Berkeley Heights, New Jersey.
Speaking at the Chemotherapy Foundation Symposium XVIII, he
reported that augmerosen (Genasense) is being tested in a phase III study in
The trial will compare the effectiveness of dacarbazine with
and without augmerosen. Randomized trials are also beginning, he noted, in
chronic lymphocytic leukemia and myeloma.
The safety of augmerosen was established in phase I/II studies
that enrolled more than 200 patients, Dr. Warrell said. The studies included
patients with breast, prostate, and bladder cancers, malignant lymphoma, and
acute myeloid leukemia, as well as the diseases targeted in the phase III
"The most common side effect is low-grade fever," Dr.
Warrell said. This occurred in 20% of patients in the phase
I/II trials but resolved within 2 days. Fatigue was noted in 10% of patients.
These adverse reactions, Dr. Warrell said, "do not overlap
importantly with side effects of current agents." This is significant, he
added, since augmerosen will be used in conjunction with standard anticancer
Augmerosen is aimed at the Bcl-2 protein, an important
inhibitor of apoptotic cell death. "Bcl-2 is widely overexpressed in many
different types of cancer cells," Dr. Warrell said.
Overexpression rises with each cycle of cancer therapy, he
Bcl-2 is a highly inducible protein and a selection phenomenon is occurring.
"In the first round of chemotherapy, the cells that are
killed are primarily Bcl-2 nonexpressing or low-expressing cells," Dr.
Warrell said. The overexpression of Bcl-2, he added, is a key element in
resistance to radiation therapy and chemotherapy.
Augmerosen uses antisense technology, he explained, to bind to
Bcl-2 messenger RNA. The resultant downreg-ulation of Bcl-2 permits the
apoptotic stimulus created by cytotoxic agents to get through to activate the
cascade toward cancer cell death (see Figure).
Profound down-regulation of Bcl-2 has been documented in the
clinical studies to date, Dr. Warrell reported.
A 90% reduction, compared with base-line, was seen in the
circulating lymphocytes of patients with prostate cancer in one study, he said.
In a patient with malignant melanoma, a downregulation of about
75% was observed at the end of a 5-day course of augmerosen given prior to
In a phase I/II study of 14 patients with malignant melanoma in
which augmerosen was given before dacar-bazine, the median survival was 13
months. Of these patients, 12 had gone through prior courses of therapy.
Objective responses were seen in 6 patients, including 1 complete response, 2
partial responses, and 3 minor responses.
A 90-Year-Old Woman
The complete response occurred in a 90-year-old woman who
received four cycles of the combination therapy. "All of her
lymphadenopathy and subcutaneous disease melted away," Dr. Warrell said.
The remaining skin lesion was removed surgically, he said, and histologic
review of the tissue showed no evidence of disease.
The dosage of augmerosen established for the phase III melanoma
trial is 7
mg/kg given by infusion daily for 5 days prior to initiation of dacarbazine
therapy. Treatment cycles are repeated every 3 weeks.