- Study Results Determine Phase 2 Dosing Regimen -
SOUTH SAN FRANCISCO, Calif., Nov. 19 /PRNewswire/ -- Raven biotechnologies, inc., a privately held company focused on the development of monoclonal antibody therapeutics (MAbs) for cancer, today announced updated results from an ongoing Phase 1/2a open-label, dose escalation clinical trial of RAV12, its lead therapeutic antibody in development for the treatment of adenocarcinomas. The objectives of the study were to define the safety profile and maximum tolerated dose of RAV12, to define the pharmacokinetics and describe preliminary efficacy.
"The study results demonstrate that a fractionated dosing regimen allows us to deliver RAV12 with an acceptable level of toxicity, while maintaining exposure that is associated with a tumor response," said George Schreiner, M.D., Ph.D., chief executive officer of Raven biotechnologies. "We are particularly encouraged to have seen a clinical response in one of the patients with advanced stage gastrointestinal cancer. These findings further demonstrate the potential therapeutic value of RAV12."
The phase 1 dose-escalation safety and pharmacokinetics (PK) trial was initiated in December 2004 in patients with recurrent adenocarcinoma who had received 1 to 3 prior treatment courses. RAV12 was administered initially four times weekly, then by fractionated dosing two or three times weekly. Thirty-three patients were treated in the dose escalation segment of the trial. Three cohorts were given a weekly dose of 0.3 mg/kg, 1.0 mg/kg, and 1.5 mg/kg, and three cohorts received fractionated dose schedules of 0.5 mg/kg twice weekly, 0.75 mg/kg twice weekly, and 0.5 mg/kg thrice weekly.
Patients all had confirmed adenocarcinoma of gastrointestinal origin or of other origin if they positively expressed the RAAG12 antigen. The majority of patients had colorectal, gastroesophageal, or pancreatic cancer. Patient responses were evaluated on day 42.
RAV12 was moderately well-tolerated with fractionated dosing that allowed delivery of an "effective dose" (i.e. 1.5 mg/kg total dose over one week time) as 0.75 mg/kg twice weekly. The two primary side effects observed were Infusion-associated abdominal discomfort and diarrhea, and elevated liver function tests. Both side effects appear related to CMax as they tended to appear early on after dosing and tended to resolve rapidly after dosing, and were ameliorated by fractionated dosing.
Treatment with RAV12 demonstrated preliminary evidence of anti-tumor activity. One patient with refractory colorectal cancer experienced a partial remission with time to progression exceeding 8 months and one patient with advanced pancreatic cancer had a > 50% reduction in the relevant tumor marker, CA19-9 and experienced disease stability for more than five months.
As a result of these findings, future development of RAV12 both as single agent and in combination with chemotherapy is planned for 2008. The recommended dose and schedule for Phase 2 clinical study of RAV12 is 0.75 mg/kg twice weekly.
RAV12 is a novel, chimeric monoclonal antibody which is directed against a primate-specific glycotope (sugar structure) that is widely displayed on the surfaces of tumor cells, particularly those of gastrointestinal origin (gastroesophageal, pancreatic, colorectal cancers). Preclinical studies have demonstrated that RAV12 may kill tumor cells in a number of ways: first, the antibody is directly cytotoxic to a human colon cancer cell line in vitro through induction of oncotic cell death, a form of cell death characterized by cell and organelle swelling and loss of membrane integrity; second, the antibody mediates antibody-dependent cellular cytotoxicity; third, the antibody mediates complement dependent cell killing; and finally, the antibody alters cellular signaling required for cell survival. RAV12 is highly efficacious in human colon, gastric, and pancreatic tumor xenograft models in vivo and has been found to be well tolerated in repeat dose primate toxicology studies.
About GI Cancers
Adenocarcinomas are malignant tumors of the epithelial cells that line glands or viscera. They typically spread by way of the circulatory or lymphatic systems and are poorly treated after metastatic spread. More than 90 percent of colon, stomach and pancreatic tumor specimens express the RAV12 defined antigen, RAAG12. Adenocarcinomas arising elsewhere, such as breast, endometrial, ovarian, lung and prostate, display the antigen to varying degrees.
Raven biotechnologies, inc. (http://www.ravenbio.com) is a privately held biotechnology company focused on the development of monoclonal antibody therapeutics for treating cancer. Raven's lead product candidate, RAV12, targets adenocarcinomas and is in clinical development for the treatment of gastrointestinal and other cancers. Raven's discovery process simultaneously identifies cell-surface drug targets and the antibody therapeutics to regulate them. Our focus on biological function allows us to rapidly identify novel target antigens and therapeutic candidates in their native configuration in the intact cell membrane. Our integrated approach is based on proprietary methods for optimizing the production of MAbs targeting cell-surface proteins, including the use of human tissue-specific progenitor and tumor stem cell lines developed at Raven.
To date Raven has identified multiple candidate therapeutic MAbs for many cancer indications including lung, colon, pancreatic, prostate, breast, brain, and ovarian cancer.
|SOURCE Raven biotechnologies, inc.|
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