Say "chemotherapy" and most people cringe, conjuring a mental picture of a sunken-eyed, hairless cancer patient who vomits constantly, breaks out in a rash and stays indoors to avoid the bright light of day.

Though somewhat dramatic, the image often is not far off the mark. But chemo - in various combinations and with biologics - works, so there's been a push lately to find other compounds that either treat the dreaded side effects or mitigate them. Witness Amgen Inc.'s Kepivance (palifermin), the keratinocyte growth factor approved late last year for mouth sores from the painful mucositis that afflicts chemotherapy patients with blood cancers who get bone marrow transplants.

Another approach targets a point further upstream. The "biomodulating" strategy tries to reduce toxicity in the first place. One such drug, Adventrx Pharmaceuticals Inc.'s CoFactor, made headlines last week. A folate-based biomodulator of the popular chemo drug 5-fluorouracil (5-FU), CoFactor gained the FDA's nod to start a pivotal Phase III trial in colorectal cancer patients. Company officials said the trial will begin late this quarter or early next.

CoFactor is the active metabolite of leucovorin, and creates more stable binding of the active form of 5-FU, FdUMP, to the target enzyme, thymidylate synthase. Joan Robbins, chief technical officer for Adventrx, formerly Biokeys Pharmaceuticals Inc., said 5-FU "has been shown in countless clinical trials to have its activity enhanced by leucovorin. CoFactor doesn't require any of the metabolic steps that leucovorin usually needs to assist 5FU, [which] can't inhibit the DNA-synthesis mechanism without this biomodulator."

In the two-arm study enrolling about 600 patients, folate-based CoFactor will be studied as a first-line, combination therapy. Half the patients will be treated with CoFactor, 5-FU and Avastin (bevacizumab), the much-touted vascular endothelial growth factor-binding antibody from Genentech Inc. that is approved for colorectal cancer and earlier this month reported good results against breast cancer, as well. The other half of patients will get leucovorin, 5-FU and Avastin.

Progression-free survival is the primary endpoint, defined as the time from start of treatment to time of disease progression or death.

"We think having the Avastin in there should make it a very attractive trial for a lot of patients, since that drug is doing quite well," Robbins said. "We're hoping to appeal to the patients who are interested in the lower toxicity level. You can keep doing your daily activities and not be quite as wiped out at the end of the day."

Robbins pointed out that 5-FU is "the backbone of chemotherapy and it will continue to be the backbone." CoFactor, she said, "goes with 5-FU wherever it's used," having nothing in particular to do with Avastin, "except the combination of CoFactor with Avastin looked very good in preclinical, compared with some of the other combinations, and we expect that to be the same in the clinic. If the docs want to use it with some of the other drugs out there, there's no reason to expect that it wouldn't" work well, she said.

"I think it's been shown over and over again now that there needs to be combinations," Robbins said. "Colorectal cancer, like all the other cancers, is a very complex disease and a single agent is very unlikely to provide all the benefit that's needed." Increasingly, physicians are layering new biologics with chemotherapies.

"There will be a lot of playing around with the schedules," Robbins said.

Adventrx also recently got the go-ahead in the UK to start an international Phase IIb trial with CoFactor in metastatic colorectal cancer, and plans to file in the first half of this year for clearance to start a Phase III study based in the European Union in pancreatic cancer.

Against the insidious pancreatic cancer, the company found encouraging results in a smattering of patients tested as part of a Phase I/II study in Sweden.

"It's a small number of patients but it's a hint of some activity, so we feel it's worth following up on," Robbins said. "5-FU plus gemcitabine had increased efficacy, but also added to the toxicity, and that's why we're enthusiastic about trying it with CoFactor. We've done a number of gastric cancers in the Swedish trials and we had some nice preliminary results."

The incidence of gastric cancer is "going up in the Western world and is a big problem in Asia," she noted.

Adventrx plans to finish the colorectal Phase III in three years, if not sooner. Getting a sufficient number of patients enrolled always is a challenge. "You do have to be creative, and we think we're pretty good at that," Robbins told BioWorld Financial Watch. "We open sites where we need to."

A Phase II trial is just finishing. Some had suggested that the study wouldn't be able to accrue patients in a timely fashion, she said, but Adventrx "enrolled it in six months." Patients, she said, "will choose lower toxicity over higher toxicity, even where their doctor doesn't necessarily recommend that. If you only have a short time [to live], you want to be in control of how you manage that time."

With 18 employees, including part-timers, Adventrx has "a couple of other drugs at the preclinical stage that are in the same category" as CoFactor, providing an understood mechanism, an established clinical benefit, and the version is some kind of advantage over the established drug, Robbins said. "None of the other molecules are first-in-class drugs, and we like that kind of profile," since the development risk is lower.

Adventrx intends to stay away from designing entirely new chemical entities.

"We're small, we're focused and we'll leave that to the guys with giant labs and lots of people," she said.