RAV12 Monoclonal Antibody Promising in GI Cancers

NEW YORK—In a phase I study, the chimeric monoclonal antibody, RAV12 (Raven biotechnologies inc) has shown preliminary evidence of efficacy in gastrointestinal (GI) tumors. Howard A Burris III, MD, director of drug development at the Sarah Cannon Cancer Center, Nashville, one of three centers where the trial is underway, spoke about the research at the Chemotherapy Foundation Symposium XXIV.

"It's always exciting to be involved in the development of a first-in-man compound. This is clearly different from many other antibodies that target growth factors," Dr. Burris said. "With the RAV12 antibody, we're looking, specifically, at being able to provide a direct cytotoxic effect."

The antibody targets the RAAG12 antigen and kills cells through oncosis rather than apoptosis (see box, The Science Behind the Study). "While RAV12 binds to some normal GI epithelial cells, it is more broadly distributed on membranes of tumor cells," he said.

The open-label dose-escalation study includes patients with metastatic or recurrent, histologically confirmed adenocarcinoma of GI origin, or another tumor type if RAAG12 positive. Patients must have had one to three prior therapies. Treatment continues until disease progression or unacceptable toxicity.

Dr. Burris reported on four treatment cohorts totaling 24 patients: The first 21 patients received RAV12 in escalating weekly intravenous doses of 0.3 mg/kg to 1.5 mg/kg over 4 weeks. Adverse events included liver function test (LFT) abnormalities, which were transient at the lower doses but more persistent at the highest dose, and infusion-related abdominal pain requiring management, which also appeared to be dose related.

Dr. Burris said the abdominal pain and LFT abnormalities may be related to Cmax. "There is recurrence with each dose, and there is a trend toward resolution between doses. Cmax can be altered by changing administration, lengthening the infusion, or fractionating the dose," he said.

To deliver a RAV12 dose equivalent to 1.5 mg/kg/wk, since efficacy is seen at this dose, fractionated dosing two to three times a week is being explored in the ongoing phase I trial. Dr. Burris' report included three patients who received

0.5 mg/kg twice weekly. When the deliverable "active dose" schedule is defined, he said, "we will enroll 15 additional patients at the maximal tolerated dose schedule to better ascertain side effects profile and toxicity."

Efficacy Results

Results to date in 18 evaluable patients have shown a partial remission in one patient and stable disease in four patients. One pancreatic cancer patient with stable disease had a greater than 50% decline in CA19-9. "She actually was clinically benefiting and received a total of nine doses of RAV12," he said, "with stable disease approaching 6 months."

The partial response occurred in a 63-year-old man with relapsed refractory colorectal cancer. He was diagnosed in 2004 with colon cancer metastasized to the lung. He was treated with FOLFOX/bevacizumab (Avastin) to progression, and then with irinotecan (Camptosar)/cetuximab (Erbitux), which was discontinued due to intolerance (diarrhea).

Single-Agent Efficacy

Starting in January 2006, the man received RAV12 at 1.5 mg/kg/wk 4. He was only recently removed from trial and generally tolerated therapy well, Dr. Burris said. With RAV12 therapy, there was a greater that 70% reduction by RECIST criteria in three pulmonary nodules. "Those responses continued to improve with more time," Dr. Burris commented.

With the observation of single-agent activity in a patient with refractory, relapsed colorectal cancer, he said, "this may be the most expeditious route to approval by the FDA for this agent." A single-agent, single-arm phase II response rate trial of RAV12 in patients with refractory colorectal cancer is currently planned.

There will also be phase II trials using RAV12 in combination with other agents, he said. Preclinical models suggest that RAV12 provides additive or synergistic effects when added to gemcitabine (Gemzar) and fluorouracil. So researchers are planning a phase II trial of gemcitabine plus RAV12 in patients with locally advanced or metastatic pancreatic cancer not previously treated.

Raven also plans to launch a phase II trial of XELOX—capecitabine (Xeloda) and oxaliplatin (Eloxatin)—plus RAV12 in patients with metastatic gastric cancer who have not been previously treated for metastatic disease, Dr. Burris said.

The Science Behind the Study

RAV12 is a high-affinity IgG1 chimeric monoclonal antibody that recognizes a primate-restricted, N-linked carbohydrate epitope (RAA12) expressed on a number of human carcinomas, including an especially high percentage (greater than 90%) of adenocarcinomas of gastrointestinal origin (colon, gastric, and pancreatic). It causes cell death through oncosis rather than apoptosis. Oncotic cell death is characterized by cell and organelle swelling and loss of membrane integrity. "The antibody causes the cell to swell up and burst," Dr. Burris said.