As expected, Celldex Therapeutics Inc. launched the randomized, double-blind, controlled Phase III trial of its cancer vaccine candidate rindopepimut (formerly CDX-110) in patients with surgically resected epidermal growth factor variant III (EGFRvIII)-positive glioblastoma.

The pivotal study, ACT IV, is expected to enroll up to 440 patients at more than 150 multinational sites to recruit 374 patients with gross total resection for the primary analysis. The endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), safety and tolerability of rindopepimut and GM-CSF in combination with temozolomide, neurologic status and quality of life.

In May, Celldex, of Needham, Mass., raised $31 million to fund the trial, which the company predicted would begin before the end of the year. (See BioWorld Today, May 19, 2011.)

In a bold move, Celldex is going it alone on the Phase III after Pfizer Inc. backed out of the firms' partnership last fall. The New York-based big pharma, which paid $50 million in cash and equity up front and would have owed up to $390 million more in milestones, cited reprioritization in returning the rights, despite the drug's impressive Phase II data in glioblastoma. (See BioWorld Today, Apr. 18, 2008, and Sept. 7, 2010.)

When Pfizer bailed, Celldex was just completing its final Phase II of rindopepimut and opted to fly solo "to keep the momentum going," President and CEO Anthony Marucci told BioWorld Today.

Since then, rindopepimut has rung up good numbers in three trials in patients with EGFRvIII-positive glioblastoma. In the ACTIVATE, ACT II and ACT III studies, median PFS from diagnosis was 14.2, 15.3 and 12.3 months, respectively, while median OS from diagnosis was 24.6, 24.4 and 24.6 months.

Mature data from ACT III, presented at last month's annual meeting of the Society for Neuro-Oncology, indicated that 52 percent of patients were alive at two years, while 50 percent of enrolled patients in both earlier studies were alive at two years from diagnosis. In contrast, historical controls treated at M.D. Anderson Cancer Center and matched for eligibility – including glioblastoma expressing the EGFRvIII oncogene – showed median PFS of 6.4 months and median OS of 15.2 months, with fewer than 6 percent surviving after two years.

The four-year survival rate for ACTIVATE is 22 percent, while follow-up in ACT II and ACT III is ongoing.

Rindopepimut was well tolerated, with injection-site reaction cited as the most frequently observed side effect.

The tumor-specific oncogene EGFRvIII confers an enhanced capacity for unregulated tumor growth and is present in many cancer cell types, but not at significant levels in normal cells. Expression of EGFRvIII is linked to poor long-term survival regardless of other factors, such as extent of resection and age. Polymerase chain reaction analysis has suggested that EGFRvIII is expressed in approximately three in 10 GBM tumors.

The ACT IV study is focusing exclusively on those patients, not all brain cancer patients – a distinction the market has somewhat blurred, Marucci said.

Celldex also worked closely with both the FDA and the European Medicines Agency to design a single global Phase III study that would pass muster with both agencies.

"We looked at endpoints that would be approvable, and we agreed upon an overall survival endpoint," Marucci said. "I think that's where the FDA has a lot of comfort these days around proving that you have a survival benefit with your drug."

ACT IV will evaluate rindopepimut plus GM-CSF added to the chemotherapeutic temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive GBM. Patients will be randomized after the completion of surgery and standard chemoradiation.

ACT IV could enroll for up to two years, Marucci said, with the company getting a look at data at 50 percent and 75 percent of events, as they occur.

Celldex expects the study to cost about $50 million. Presently, the company has about $62 million in cash, which should see it into 2013 without additional fundraising or partnerships, Marucci said. The biotech has a pipeline of products in cancer, inflammatory disease and infectious disease based on its antibody-focused precision targeted immunotherapy platform and could begin looking to partner some candidates in the interim, he added.

For example, the company expects to complete a Phase II of CDX-011 , a human monoclonal antibody-drug conjugate that targets glycoprotein NMB, in metastatic breast cancer by the end of the year and report those data in mid-2012. Discussions with potential partners are already under way for that compound and others with broader indications than rindopepimut, Marucci said.

Celldex now plans to market rindopepimut in the U.S., since the community of centers treating brain cancer is small enough to lend itself to a modest sales and marketing force, he added. However, the company will seek a partner for other markets.

Rather than waiting for complete data from the pivotal trial, Celldex plans to launch a Phase II study of rindopepimut in combination with Avastin in patients with recurrent glioblastoma. The ReACT study will begin enrolling patients later this month or in early January and run about 12 months, providing the company with important additional data, Marucci said.

The company's stock (NASDAQ:CLDX) started slowly on Thursday, but gained steadily throughout the day, finishing up 15 cents, to close at $2.81.

In a research note, Roth Capital Partners analyst Joseph Pantginis predicted the compound and the company have more life in them. "We view the opening of ACT IV as an incremental positive for Celldex," he wrote, adding, "We believe that Celldex is solidifying its position as a premier cancer immunotherapy company."