Bcl-2 Antisense Response in Melanoma Called ‘Remarkable’

February 1, 2003
Oncology NEWS International, Oncology NEWS International Vol 12 No 2, Volume 12, Issue 2

NEW YORK-An antisense oligonucleotide directed against Bcl-2 is yielding "remarkable" responses in specific melanoma patients enrolled in a phase III trial, according to Anna C. Pavlick, DO, assistant professor of medicine, New York University School of Medicine.

NEW YORK—An antisense oligonucleotide directed against Bcl-2 is yielding "remarkable" responses in specific melanoma patients enrolled in a phase III trial, according to Anna C. Pavlick, DO, assistant professor of medicine, New York University School of Medicine.

The multicenter, randomized, controlled phase III trial of the agent, known as G3139 (Genasense, Genta Inc./Aventis), is accruing patients rapidly and is near completion, Dr. Pavlick said at the Mount Sinai School of Medicine Chemotherapy Foundation Symposium XX.

"Responses have been impressive," Dr. Pavlick said. "Clearly, this is a trial that needs to be completed . . . we really need to know if the effects that I’m seeing as a single investigator are truly seen in other institutions as well."

All patients in the phase III trial are chemotherapy naïve and must have stage IV disease with no brain metastases. If they have no distant disease, they must be considered surgically nonresectable.

Arm A of the trial includes chemotherapy with dacarbazine (DTIC), currently the only FDA-approved chemotherapy as a single agent for melanoma, at a dose of 1,000 mg/m2 on day 1 of a 21-day cycle. Arm B is the G3139 antisense protein, given as a 7 mg/kg continuous infusion on days 1 through 5, plus DTIC on day 6 of a 21-day cycle. Treatment is for up to eight cycles, although patients are allowed to remain on therapy if they are still responding.

Dr. Pavlick’s first patient on G3139 was a woman with extensive metastatic disease, with "tremendous" subcutaneous nodules along the right leg and a large pelvic mass. Imaging performed after three cycles showed complete resolution of the pelvic node.

"This patient had completed 16 cycles of chemo with G3139 and stopped treatment," she said. "It will be 1 year as of next month that she still remains disease-free off all treatment."

Antisense agents work by inhibiting specific, isolated proteins. Under normal conditions, DNA makes RNA, which in turn encodes a protein. Antisense agents bind with the RNA, prohibiting manufacture of a protein. In the case of G3139, that protein is Bcl-2, which is overex-pressed in many tumor types. Bcl-2 prevents apoptosis by blocking release of the caspase trigger cytochrome C from mitochondria.

Preclinically, G3139 showed single-agent activity in a broad spectrum of cancers, since most cancers overexpress Bcl-2, Dr. Pavlick said. Synergy with chemotherapy, chemo-radiotherapy, and even antibody agents had also been observed.

Recommended clinical doses of G3139, based on phase I/II trial results, are 3 to 7 mg/kg/d, given as continuous infusion for 5 to 7 days. "There is variation in dosing, because we found that lymphoid malignancies, namely chronic lymphocytic leukemia and non-Hodgkin’s lymphoma, are exquisitely sensitive to G3139 and require lower doses," Dr. Pavlick said.

Pharmacokinetic analysis of the anti-sense agent showed that with continuous infusion, maximal concentrations increase as the dose increases. The half-life is approximately 2 hours, and steady state levels are achieved in about 10 to 12 hours. "Any dose over 2 mg/kg/d gives you therapeutic dosing levels," she said.

Published clinical data on G3139 in melanoma includes a phase I/II study of 14 patients with metastatic disease; 12 had prior therapy (chemotherapy, interferon, or interferon and radiation therapy). Responses were noted for 6 of the 14 patients (Jansen et al: Lancet 356:1728-1733, 2000). "Even more impressive" was the median survival of 17 months, including a durable complete response of 2 years in one patient, Dr. Pavlick said.

She noted that in the melanoma literature on previously treated patients after second- or third-line therapy, overall survival is only about 6 months. "To come out with a 17-month survival, even if it is a partial response, clearly shows the activity of this drug in melanoma," Dr. Pavlick said.