By Debbie Strickland

Special To BioWorld Today

ATLANTA – A gene therapy treatment for cancer is heading into Phase III trials as a result of “robust” Phase II data disclosed Monday at the American Society of Clinical Oncology’s annual meeting here.

Introgen Therapeutics Inc. and RPR Gencell reported early data from three Phase II trials that enrolled a total of 170 patients with recurrent squamous cell head and neck cancer. They were ineligible for surgical removal of their tumors. The gene therapy targeted the p53 gene.

In the largest study, 106 patients with advanced head and neck cancer were treated, about 50 percent of whom had tumors refractory to chemotherapy and/or repeat radiation therapy. Of 90 evaluable patients, five had complete or partial response and 18 achieved stable disease that was maintained from two to 11 months.

While there was no control arm to the study for comparison, John Nemunaitis, a study investigator, noted that the median survival time of patients with recurrent head and neck cancer under currently available treatments is less than six months, while the median achieved in the Phase II p53 studies was seven months. Nemunaitis is regional director of PRN Research Inc. in Dallas and director of Texas Oncology Physician Association Research.

“No treatment to date has ever shown an improvement in these statistics,” he said. “The fact that this novel approach, as a single agent, seems to show some therapeutic benefit beyond the six-month mark is good news.”

“The take-home message from our very broad and robust Phase II,” said James Merritt, vice president of clinical affairs for Introgen, “is that we treated tumors of very substantial size in a wide variety of locations, including adjacent to mucosal areas in the oral and pharyngeal cavities.”

Head and neck cancer was a natural choice as lead indication for the product, Merritt told BioWorld Today.

“Our product is administered intra-tumorally, and therefore the product concept is local regional cancer control,” Merritt said. “Head and neck cancer is a disease in which local and regional manifestations predominate, even when the disease is far advanced. It is also a condition, namely advanced head and neck cancer, that desperately requires new therapies.”

Phase III protocols still are under development, but the companies noted that in Phase II, adenovirus-delivered p53 appeared to work better in patients with tumors smaller than 7.5 cm and with a more frequent or intense dosing regimen.

Looking toward Phase III, Merritt said, “We do think that a size restriction of tumors may be appropriate, but we do not wish to restrict tumor size so much that we lose sight of the common variety of patient that’s out there. In other words, we believe that treating very small tumor deposits in soft tissue may be where the product is most effective, but most patients have more substantial lesions with a wide distribution within the head and neck.”

Data Are A Gene Therapy Milestone

The results are a shot in the arm for the gene therapy field, which has drawn its share of skepticism.

“Our results,” said Merritt, “support the idea that current generations of gene replacement therapy can be safely administered and result in biological activity and relevant clinical activity.

“All of us in the field recognize that the current versions of gene therapy, and particularly the vectors which are used to direct genes to the proper locations, are suboptimal,” Merritt said. “The ongoing debate is between those who would seek to exploit and commercialize early versions of gene therapy [such as Introgen and RPR] vs. those who are more interested in basic vector construction and further research into the scientific principles.”

Still privately held after a 1996 IPO attempt was scuttled, Introgen, of Austin, Texas, recently established a wholly owned London subsidiary, Gendux Inc., to develop academic and corporate collaborations in Europe. The company is pursuing other gene therapies, including adenovirus delivery of the PTEN tumor-suppressor gene.

RPR Gencell is the gene therapy division of Collegeville, Pa.-based Rhone-Poulenc Rorer Pharmaceuticals Inc.

In other news from ASCO:

• Aronex Pharmaceuticals Inc., of The Woodlands, Texas, presented preliminary Phase II results for Platar, a liposomal formulation of a novel platinum drug designed to overcome the toxicity and drug resistance that limit the usefulness of platinum as a chemotherapeutic agent. In 17 patients with malignant pleural mesothelioma, a complete response based on biopsy and cytology was seen in 61 percent and 71 percent of patients, respectively (compared to a response rate of 10 percent to 15 percent for currently available therapies).

• Biomira Inc., of Edmonton, Alberta, released the final analysis of a bridging study with an enhanced formulation of its Theratope cancer vaccine, indicating higher titres in a greater percentage of patients, thus validating the company’s decision to use the improved formulation in the 900-patient pivotal Phase III trial now under way. The formulation utilizes Hamilton, Montana-based Ribi Im munochem Research Inc.’s Detox-B adjuvant.

• Celgene Corp., of Warren, N.J., said researchers investigating the use of Thalomid (thalidomide) found in separate studies that the drug has activity in recurrent glioblastoma multiforme (GBM), and that it appears to boost quality of life in patients with advanced cancers. Of 45 patients evaluated for efficacy in a Phase I/II GBM trial, all but 12 achieved stable disease or tumor regression. A separate Phase I/II monotherapy trial looked at the drug’s effect on quality-of-life measures in terminal cancer patients, finding that after 10 days of treatment all measures improved by more than 30 percent.

• Dendreon Inc., of Seattle, said Phase II results for its dendritic cell therapy for prostate cancer, APC8015, indicate positive responses in patients with advanced hormone-refractory disease. The trial treated 28 men with intravenous APC8015 monthly for three months. The product was safe and well-tolerated, and stimulated immune responses in all patients. It also significantly extended time to disease progression.

• Genentech Inc., of South San Francisco, updated Phase III trial results in metastatic breast cancer for Herceptin (trastuzumab), an FDA-approved anti-HER2 antibody. At a median follow-up of 29 months, overall survival in patients treated with Herceptin plus chemotherapy (anthracycline and cyclophosphamide [AC] or paclitaxel) was 25.4 months as compared to 20.3 months in patients treated with chemotherapy alone.

• ImClone Systems Inc., of New York, said two Phase Ib/IIa studies of the monoclonal antibody C225, an inhibitor of the epidermal growth factor receptor, demonstrated clinical responses in combination with standard agents. Five of nine refractory squamous cell head and neck cancer patients treated with C225 and cisplatin achieved partial responses and one achieved a complete response. In a trial combining C225 and radiation therapy in 15 patients with locally advanced head and neck cancer, 13 achieved complete responses and two achieved partial responses.

• Magainin Pharmaceuticals Inc., of Plymouth Meeting, Pa., said data from its ongoing Phase I trial of the anti-angiogenic inhibitor squalamine showed the drug was well tolerated in the 39 advanced cancer patients enrolled to date. Phase II studies should begin this quarter.

• MGI Pharma Inc., of Minnetonka, Minn., said its MGI 114 showed significant antitumor activity in patients with hormone-refractory prostate cancer. Sixteen of 21 evaluable patients have shown stable or decreasing PSA levels.

• Myriad Genetics Inc., of Salt Lake City, said none of the 131 patients who had BRCA1/2 genetic testing reported her health insurance rates were raised or cancelled, regardless of the test result.

• Onyx Pharmaceuticals Inc., of Richmond, Calif., updated and confirmed efficacy data from a Phase II trial combining its viral therapeutic, ONYX-105, with cisplatin and 5-FU in patients with recurrent tumors of the head and neck. Data showed the combination with ONYX performed better than the chemotherapy drugs alone.

• OSI Pharmaceuticals Inc., of Uniondale, N.Y., said data from two Phase I trials of CP-358,774, an oral inhibitor of epidermal growth factor receptor tyrosine kinase, showed therapeutically relevant levels of drug were achieved. OSI and partner Pfizer Inc., of New York, have begun Phase II trials.

• SunPharm Corp., of Ponte Vedra, Fla., and the Parke-Davis division of Morris Plains, N.J.-based Warner-Lambert Co. will expand trials of CI-1006 (diethylnorspermine), a polyamine analogue, for treating solid tumors. The decision follows demonstration of a modest degree of tumor shrinkage in a Phase II trial in renal cell carcinoma.

• Techniclone Corp., of Tustin, Calif., said six of 12 brain cancer patients had shrinkage or stabilization of their tumors after treatment with Cotara, a drug labeled with iodine-131 that binds to decaying tumor cells. Phase II studies are under way in malignant glioma and in solid tumors. n