New Genta trial has link to Taxol.
Genta to Commence Phase I/IIa Prostate Cancer Trial Of bcl-2 Antisense Compound Administered with Mitoxantrone
SAN DIEGO--(BUSINESS WIRE)--Nov. 17, 1998--Genta Incorporated (Nasdaq: GNTA) today announced it has initiated a new Phase I/IIa study of its lead development compound G3139 at the BC Cancer Agency Vancouver Cancer Centre in British Columbia, Canada. The study will examine the safety and efficacy of G3139 in the treatment of hormone-resistant, metastatic prostate cancer, when administered with mitoxantrone, a chemotherapeutic agent often used to treat advanced prostate cancer. The investigators are Dr. Richard Klasa and Dr. Kim Nguyen Chi of the BC Cancer Agency's Division of Medical Oncology and Department of Advanced Therapeutics.
Prostate cancer is the most common malignancy in men in the United States and the second leading cause of death behind lung cancer. While hormonal therapy is initially very effective, the disease-free interval has a median duration of 18 to 24 months. Moreover, the overall survival for patients once they are found to be androgen-insensitive is only 6 to 9 months.
"The research team at the BC Cancer Agency has conducted preclinical studies of G3139 in prostate and other cancers," Dr. Klasa says. "We are eager to explore its potential in patients. A key direction of the Agency and the Department of Advanced Therapeutics is to advance the development of new approaches to cancer treatment and make them available to the people of B.C.," Klasa continues. "Our vision, however, is more global - to advance the treatment of cancer for people everywhere. This study could play a crucial part in making that vision a reality."
The preclinical work studying G3139 in prostate tumor models was performed in the BC Cancer Agency and Vancouver General Hospital laboratories of Dr. Klasa's collaborator Dr. Martin Gleave, Associate Professor of Surgery at the University of British Columbia. "These studies implicate Bcl-2 as an important mediator of hormone refractory disease," says Dr. Gleave. "G3139 silences bcl-2 gene expression in a dose-dependent and sequence specific manner, and significantly delays the time to androgen-independence. Additionally, antisense oligonucleotides to Bcl-2 increase the sensitivity of cancer cells to traditional cytotoxic chemotherapeutic agents, including taxol and mitoxantrone, providing preclinical support for this Phase I/IIa study at the BC Cancer Agency." The Agency's prostate research group presented these findings last spring at the American Association for Cancer Research annual meeting and at the American Urological Association meeting. The latter presentation was awarded the Capcure Research Prize for the best prostate cancer presentation at the meeting.
"Genta has had a long-standing research relationship with both Dr. Klasa and Dr. Gleave. We are very pleased to continue this productive collaboration into the clinical development phase," says Kenneth G. Kasses, Ph.D., Genta's President and CEO. "We are rapidly expanding our efforts in the development of G3139 used together with chemotherapeutic agents. We hope studies such as this will provide key information on the safety and efficacy of G3139."
Background Information on Apoptosis, Cancer, Bcl-2 and G3139
The body's cells are normally programmed to detect damage in their genetic makeup and to enter into a suicidal state when such alterations are detected. This natural process, known as apoptosis or "programmed cell death," helps the body regulate its own well being by destroying damaged cells. In many cancer cells, however, this process of natural cell death is inhibited by the over expression of a protein called Bcl-2, which is produced by a gene identified as bcl-2. Consequently these cancer cells, even though damaged, resist dying and continue multiplying.
In many cases, cells that over produce the Bcl-2 protein are also resistant to chemotherapeutic agents, many of which act by stimulating apoptosis, and these cancers have been associated with an unfavorable prognosis. For example, it has been reported that Bcl-2 protein is over produced in virtually all hormone-refractory, metastatic prostate cancer; 80-90% of estrogen-receptor-positive breast cancer; 70-100% of follicular lymphomas; and up to 90% of malignant melanomas. Bcl-2 has also been reported to be up regulated in some lung, gastric and colorectal cancers.
Using a single drug based on the genetic sequence of the bcl-2 gene, Genta Incorporated is developing a novel therapeutic approach to treating several cancers. Genta developed this synthetic DNA-like molecule, identified as G3139, to bind specifically to a small segment of the messenger RNA, which produces the harmful Bcl-2 protein. Once bound to the messenger RNA, the messenger RNA is destroyed, preventing the production of the Bcl-2 protein. (This type of interference with the process, whereby genes produce proteins through their messenger RNA, has been called "antisense.") The goal of this therapeutic approach is to restore the diseased cells' sensitivity to apoptotic stimuli, including many chemotherapeutic agents - an effect called "chemosensitization."
In February 1998, a report of such chemosensitization appeared in Nature Medicine, a peer-reviewed, scientific journal. In the report, G3139 was shown to enhance the effect of a standard chemotherapeutic agent, DTIC or dacarbazine, in a mouse model of human malignant melanoma. In two experiments with a total of 13 animals, 10 had no tumor after the combined treatment and the other three showed an average reduction in tumor weight of 90% compared to the DTIC-alone treated, control animals.
Genta is now in the clinical development phases of G3139. A Phase I study at the Royal Marsden Hospital in London has been completed, and a Phase I/IIa study is in progress at the Memorial Sloan-Kettering Cancer Center in New York City. A preliminary report of the study at the Royal Marsden was published in The Lancet in April 1997. Although this was primarily a safety study, the investigators reported very encouraging biological clinical activity of the drug, including one complete response to G3139 alone. The first combination drug trial using G3139 and DTIC in malignant melanoma is in progress at the University of Vienna conducted by the same investigators who published the work cited in Nature Medicine, above. Other clinical studies are also in development and should be initiated in the coming months.
Genta Incorporated (Nasdaq: GNTA) is a biopharmaceutical company focused on building a product and technology portfolio based on its Anticode(tm) (antisense) products intended to treat cancer at its genetic source. |
