Cancers of the pancreas and esophagus may not be the top-rated killers among malignancies, but they are the most unforgiving. To wit:

"Pancreatic cancer," observed Henrik Rasmussen, senior vice president of clinical research at GenVec Inc., of Gaithersburg, Md., "is a horrible tumor type with a very poor prognosis. The only way you can possibly cure pancreatic cancer is by surgery. The problem is that at the time of diagnosis, very few patients are eligible for surgery, because the tumor has already either spread, grown into surrounding tissue, is too close to major blood vessels, the liver or the major nerves in the back of the abdomen. The incidence of pancreatic cancer," he continued, "is about 30,000 new cases in the U.S. per year, with approximately 29,800 deaths. That gives you an indication of how horrible a tumor it is.

"The incidence of runner-up esophageal cancer," Rasmussen added, "is around 13,000 per year. And the mortality rate is very close to the incidence - some 12,500 deaths a year - almost as bad as pancreatic. Its epidemiology is changing. Esophageal used to be a blue-collar cancer related to smoking and alcohol consumption. Now it's moving up into the white-collar arena, where the incidence is rapidly rising among white-collar people, not due to smoking or alcohol but to acid reflux from the stomach."

Genvec Shifts Into Clinical

GenVec is moving too, from preclinical rodent testing of its flagship anticancer drug, TNFerade, to clinical trials. The Journal of Clinical Investigation (JCI) for August 2002 reports the company's latest preclinical experiment under the title: "Transcriptional control of viral gene therapy by cisplatin." Its senior author is radiation oncologist Ralph Weichselbaum, at the University of Chicago. He is a paid consultant to GenVec.

"What Weichselbaum showed," Rasmussen told BioWorld Today, "was that he had one group of tumor tissue from mice that received the combined anticancer treatment of cisplatin and TNFerade. Another group was given only TNFerade. He found higher secretion of TNF-alpha in the animals that got TNFerade plus cisplatin; also an increase in the anticancer activity. What the paper in JCI showed," Rasmussen continued, "was that not only can we activate the radiation-inducible promoter by radiation. We can also induce it by cisplatin.

"TNFerade," he explained, "is a modified adenovirus from which we have deleted the pieces of DNA, which the virus needs to divide and put into the replication-disabled virus the gene encoding the human tumor necrosis factor. And we have also incorporated the so-called Egr-1, the radiation-induced promoter into the construct as well. Back in the early 90s, a number of clinical studies were done using the recombinant TNF-alpha protein in various cancer types. It was found that it did have potent anticancer activity, but it was horribly toxic as well. So we have tried to find ways by which we could capitalize on the well-known anticancer activity of TNF-alpha without the toxicity. And the data we have generated so far supports that notion. We think that by using a gene therapy construct, which basically is transporting the gene into the tumor cells, and putting in a radiation-inducible promoter as well, we can give very high localized levels of TNF-alpha inside the tumor microenvironment, without any systemic spillover."

The American Society of Clinical Oncology (ASCO) was the first to learn last May of GenVec's initial clinical trial. "Our Phase I trial is completed now," Rasmussen recounted. "We treated 37 patients with a variety of tumor types, including non-small-cell lung cancer, breast cancer, pancreas, colorectal, melanoma and sarcoma at different dose levels. We presented preliminary results from that study at ASCO back in May. What was remarkable with that study was that we saw very high response rates, which is unusual of course in oncology Phase I safety studies. We were treating patients who had failed everything else, and who were in very bad shape.

"The response rates reported with other anticancer agents in Phase I studies are normally pretty low. We were gratified by the very high response rates we saw. At the time we presented at ASCO, we had 22 patients available. And we found a complete response in five of 22 with total disappearance of the injected tumor tissue inside those 22 patients. It's what is called a partial response, that is, a reduction in the tumor size between 50 percent and 100 percent in seven patients. Another five patients had a tumor shrinkage of between 25 percent and 50 percent from baseline.

"All told, in 17 of 22 patients at four sites we saw significant tumor shrinkage - very unusual in a Phase I study. The study also showed us that the TNFerade was very well tolerated. We injected it directly into the tumor mass. Only mild, transient toxicity was seen, even at the high doses we used."

Rasmussen went on: "In our Phase I study, we included four patients with pancreatic cancer and saw significant tumor shrinkage in three of the four. That encouraged us to go after pancreatic cancer in a randomized Phase II clinical trial. We started that study three weeks ago, involving 22 institutions throughout the U.S. and up to 150 enrollees. We're looking at a range of differet endpoints including tumor shrinkage, progression-free survival, quality of life, as well as the possibility of making a nonresectable pancreatic tumor resectable.

So we are taking those patients who are deemed to be inoperable and treating them with radiation and 5-fuorouracil (5-FU) plus TNFerade. We call this trial Phase IIb because it is actually randomized."

Aiming For Autumn Phase II Trial

"The next step we are planning is to start a Phase II trial in esophageal cancer. We hope to launch that study some time this fall. And we are looking into the possibility of starting other Phase II studies, possibly head an neck cancer as well. And depending on the results of those trials, if they are very positive, then we move into Phase III efficacy studies. There is no doubt now in our mind that TNFerade can shrink tumors. The key challenge from a development point of view is to demonstrate that we can translate tumor shrinkage ability into an increase in survival or improvement in quality of life." He concluded: "Those are the endpoints the FDA is going to look at."