Author: Catherine Shaffer

Cel-Sci Corp. began a carefully designed Phase III trial of Multikine, its investigational immunotherapy for head and neck cancer. Because Multikine is designed to recruit the support of a mostly healthy immune system, Cel-Sci is making a headlong charge at the goal of first-line therapy, instead of trying to develop the product in patients who have already received surgery, radiation and chemotherapy, and have suppressed or damaged immune systems as a result. If Cel-Sci can prove the therapy works in the narrow three-week testing window granted by the FDA, Multikine stands to replace a standard of care that has changed little in half a century.

“It makes no sense to develop an immunotherapy product for late-stage patients. You should develop it as a first line therapy, ahead of radiation or chemotherapy,” Cel-Sci CEO Geert Kersten told BioWorld Today.

Vienna, Va.-based Cel-Sci’s clinical trial plan takes advantage of a nearly inevitable delay of up to six weeks between diagnosis and surgery in most head and neck cancers. The FDA has allowed Cel-Sci a three-week period to give Multikine to patients before they commence with surgery, radiation, and chemotherapy. This will not deprive any patients of the best possible standard-of-care while they also try an experimental therapy.

Head and neck cancer strikes about 500,000 people annually worldwide. Some causal factors include smoking, drinking and chewing tobacco. Most cases are diagnosed outside the U.S., and about two-thirds of patients appear with advanced disease. The standard treatment for it is surgery followed by chemotherapy with platinum-based drugs (carboplatin or cisplatin) and radiation, which is sometimes done concurrently with chemotherapy. The protocol is arduous, to say the least, and typically only extends survival by six or seven months.

Most immunotherapies are antibodies specifically targeted at a type of cancer cell. Multikine is a mixture of natural cytokines that Cel-Sci said simulates the body’s immune response. It includes interleukins, interferons, chemokines and colony-stimulating factors.

The trial will enroll 880 patients at 48 clinical centers in the U.S., Canada, Hungary, Poland, Ukraine, Russia, India, Israel and Taiwan. According to Kersten, the trial design is highly portable because the same standard of care for head and neck cancer is used around the world.

Cel-Sci partners Teva Pharmaceutical Industries Ltd., of Jerusalem, and Orient Europharma Co. Ltd., of Taiwan, will carry out studies in Israel and Taiwan, respectively, under the supervision of Cel-Sci’s global contract research organization.

Cel-Sci has not partnered Multikine in major markets like the U.S. and Europe. “We can sell ourselves there,” said Kersten. Teva and Orient will help Cel-Sci access markets in the developing world. Taiwan, especially, will be an important market, since the use of betel nut (a mild stimulant) in that country leads to a high rate of head and neck cancers.

In order to maximize Multikine’s chances of approval, Cel-Sci selected overall survival as its endpoint. Overall survival is the most bullet-proof of clinical endpoints, and, said Kersten, “Survival is the endpoint [FDA regulators] want to see these days.”

In Phase II studies, Multikine boosted overall survival by 33 percent over standard of care. Patients in the Phase II study included those with advanced primary head and neck cancer who were scheduled for their first treatment, and they were given Multikine for three weeks before the standard course. Results from the study were published in the May 2005 edition of the Journal of Clinical Oncology. The median follow-up period for the patients was 3.2 years. Survival and two-year local regional control beat the rates reported in scientific literature from 39 trials between 1987 and 2004. (See BioWorld Today, Feb. 22, 2006.)

Based on the Phase II results, Cel-Sci is optimistic about hitting statistical significance with at least a 10 percent increase in survival.

Multikine’s route of administration also differs from other immunotherapies, which are given intravenously. According to Kersten, the goal is to stimulate a localized immune response at the site of the tumor.

The therapy is injected in the vicinity of the tumor not in the tumor itself. There are two reasons for that. One is that injection directly into the tumor risks dispersing tumor cells. The second, larger reason, is that Cel-Sci is attempting to target the therapy at micrometastases that form outside of the main tumor.

It is micrometastases that cause recurrence, said Kersten, because they can’t be removed surgically. The Multikine strategy for increasing survival is to decrease the odds of metastasis by wiping out the micromets at the very earliest stage.

Kersten said that the drug has been given to 220 patients to date, with no serious adverse events. The low toxicity of Multikine will be an asset to patients who will be subjected to the highly toxic standard-of-care regime later. “Our drug wouldn’t work if it had any toxicity. You can’t add a toxic drug to anything that is horribly toxic,” he said.