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Celldex Touts Brain Cancer Vaccine Data, Talks FDA Strategy

Xconomy New York — 

It’s notoriously tough to develop just about anything that helps patients with glioblastoma, an aggressive brain cancer, live longer. It’s just as hard to develop a vaccine that provides any sort of benefit to cancer patients. Yet Hampton, NJ- and Needham, MA-based Celldex Therapeutics (NASDAQ: CLDX) is providing some data today indicating that it just might have a chance to do both.

Celldex is reporting interim results today from a Phase 2 trial showing that its vaccine, rindopepimut, or “rindo,” helped extend the lives of a small group of glioblastoma patients who have relapsed after surgery, chemotherapy, and radiation. The headline number for Celldex is that patients in its study taking rindo along with bevacizumab (Avastin)—the only approved therapy for this group of patients—survived for a median of 12 months, compared to 8.8 months for those getting bevacizumab alone.

Celldex said the 3.2-month benefit was statistically significant, meaning it was unlikely to be due to chance. Rindo also hit statistical significance in helping slow the progression of these patients’ tumors. Some 27 percent of those on bevacizumab and rindo in the trial had their tumors held in check after six months of treatment, compared to 11 percent of those in the other group.

There were no serious adverse events associated with the drug; Celldex only reports that one patient had a grade 1 (mild) brain bleed; its chief medical officer, Thomas Davis, says the bleed didn’t seriously impact that patient. The most significant side effects so far have been an “occasional” grade 2 (moderate) allergic reaction, he says. Celldex is reporting that the vaccine was well tolerated in its study.

While a 3.2-month survival benefit may not seem like much, people with recurrent glioblastoma often live for only a handful of additional months. There aren’t many treatment options, because, for one, the tumor is hiding behind the blood-brain barrier and it’s hard for many chemotherapy drugs to get there.

Patients first get surgery, radiation, and the chemotherapy drug temozolomide. If their tumors return or progress after that, the options are more surgery, a variety of off-label chemotherapies, and bevacizumab. All in all, however, glioblastoma is an aggressive, fast-moving cancer that often kills people in 15 months or less from the time of initial diagnosis, and some six months or so after their cancer recurs.

“I’m pleased to see this; I would say it’s a real advance,” says Donald O’Rourke, an associate professor of neurosurgery at Penn Medicine, who isn’t involved with Celldex. “Once you get a recurrence [of glioblastoma], it’s a really difficult population of patients to treat. Patients who recur from this tumor are typically on steroids and their immune systems are not functioning well. They’ve been treated a lot, and would not be the group of patients you would expect to see any kind of immune response, and yet [here] they are [responding].”

The data have Celldex thinking bold. The company will now follow the patients in the study for another three to six months before reporting final results. If the results hold up, Davis says Celldex may talk to the FDA about the possibility of “accelerated approval”—as in, on a thinner body of evidence than the agency usually requires, enabling the drug to get to market faster than it would otherwise.

“If the final data are consistent, we believe the results of this study are very significant for patients and the field,” he says. “This would be an innovative license application, but could be justified by the circumstances.”

Rindo is a cancer vaccine that stimulates an immune response against EGFRvIII, a mutated molecule found on tumor cells in about 30 percent of patients with glioblastoma. Because this molecule is only present on tumor cells, the treatment can theoretically kill tumor cells while sparing healthy ones. Celldex CEO Anthony Marucci estimates that about 3,000 patients in the U.S., and 6,000 in Europe, have glioblastoma with an EGFRvIII mutation. The cancer recurs for most of them.

“Targeted therapy has been very successful in melanoma, in breast cancer, in a lot of the leukemias and lymphomas, where the actual mutations are being targeted,” O’Rourke says. If it were to end up getting approved, “to my knowledge, this would be the first approval of a targeted therapy [in glioblastoma] where the goal of the therapy is to induce an immune response against a specific mutation in the tumor.”

Celldex’s vaccine has a fairly long history. The company, which was spun out of Medarex (now owned by Bristol-Myers Squibb) several years ago, cut a deal with Pfizer in 2008 to co-develop it. Pfizer bailed on rindo (then known as CDX-110) two years later, sending Celldex shares spiraling downward, but the company has continued its development. Rindo is the furthest along of a group of immuno-oncology drugs Celldex is trying to advance.

Celldex aims to position the vaccine both as a front-line treatment, in combination with temozolomide, and for patients who relapse. A phase 3 trial testing rindo for newly-diagnosed brain cancer patients is expected to produce interim data in mid-2015. Celldex decided to try testing the vaccine in people who’ve relapsed after temozolomide therapy only after some patients who weren’t eligible for its studies but received the treatment under a “compassionate use” program—sicker patients, whose tumors had continued to grow despite radiation and chemotherapy—appeared to have some benefits. The idea was to see if rindo could be used on even the sickest of glioblastoma patients: those who were just about to go on bevacizumab, and those who hadn’t responded to it.

“We looked at this study as a challenge,” Davis says.

This is also the first rindo study Celldex has reported data from with a control arm. The other mid-stage trials it ran, in newly-diagnosed glioblastoma patients, were all single-arm trials comparing survival figures to “historical” control groups.

In this trial, Celldex divided patients into a few groups. The first group of 72 patients hadn’t taken bevacizumab yet. They were randomized, to receive either rindo and bevacizumab, or bevacizumab alone. Celldex then enrolled 25 patients into a second arm to see how the drug would fare in patients whose disease had progressed despite treatment with bevacizumab, where there are no approved therapies. After seeing a couple of responses in that group to treatment last year, Celldex added another 28 patients into it, with the idea of deciding whether or not to continue developing the drug there if the data looked good.

Celldex saw what it was hoping to see for patients who hadn’t taken bevacizumab. But for the sicker patients—those whose cancer progressed despite treatment—it didn’t. Though there were some signs of activity in those patients, Davis says Celldex hasn’t seen any additional responses in that group since the first few it reported last year, so it’s going to focus on other stages of brain cancer progression.

“Realistically, knowing that we’ll have data from other studies and have pretty good data in [patients who hadn’t taken bevacizumab yet], it doesn’t really make sense for us to expand [the other group] at this point anyway,” he says.

If the data for the other patient groups hold up, and Celldex can continue to show a benefit, it would be bucking a trend. There is a long list of cancer vaccines that have flopped in clinical trials, among them GlaxoSmithKline’s MAGE-A3, and Merck KGaA’s Stimuvax. While Celldex still has a long way to go, it’s taken one step closer than most.

“It’s a phase 2 study, it’s not a large study, and it’s not final data, but right now we do think the data are very exciting,” Davis says.