Health and Prostate

Cell Genesys’s GVAX vaccine for CaP consists of tumor cells that have been irradiated and genetically modified to secrete GM-CSF, a hormone that plays a key role in stimulating the body’s immune response. Unlike Provenge, the vaccine is not patient-specific and is administered by intradermal injection, making it significantly more convenient to deliver and less expensive to manufacture.

GVAX has completed a Phase II trial, and the first of two planned Phase III trials among patients with metastatic, hormone-refractory CaP is ongoing. The ongoing Phase III trial (Vaccine ImmunoTherapy with Allogeneic CaP Cell Lines [VITAL-1]) aims to enroll 600 chemotherapy-naive, asymptomatic patients and will compare GVAX vaccine with taxane chemotherapy to determine the survival benefit. Patients will receive intradermal injections of the vaccine every two weeks for up to six months. The second trial (VITAL-2) will enroll symptomatic patients and compare the effect of GVAX vaccine plus taxane chemotherapy with that of taxane monotherapy on palliation of bone pain. Both trials will enroll patients at all levels of the Gleason score.

In May 2004, the FDA granted Cell Genesys a special protocol assessment (SPA) for VITAL-1. The SPA is an indication that the FDA agrees that the trial’s design is adequate to support a biologies license application (BLA) and that the study findings will allow a definitive assessment of GVAX’s effectiveness. The trial aims to achieve a 33% improvement in overall survival. The company initiated the second trial in 2005.

At ASCO 2004, investigators presented mature results from a Phase II trial of GVAX involving 80 patients with hormone-refractory CaP with evidence of metastasis to the bone and other sites. Patients received treatment for 24 weeks in a dose-escalation trial. Doses ranged from 100 million to 300 million cells every two or four weeks; patients in the highest-dose group also received an initial dose of 500 million cells. Vaccine-specific antigenic protein antibodies and a marker of osteoclast activity (type I carboxy-terminal telopeptide [ICTP]) were measured at weeks 12 and 14. At a median of 12 months, no dose-limiting toxicities had been observed and median survival had not been reached. Thirty-two percent of patients in the high-dose arm achieved PSA declines following repeat vaccinations. Of all patients, 62% had stable or declining ICTP levels, suggesting osteoclast inhibition. Bone scans showed stabilization of disease in 43% of patients; two patients had completely normal bone scans. Immunogenicity appears to be dose-dependent: 87% of the patients in the high-dose group achieved an immune response to at least one cell line, compared with 72% and 40% in the medium- and low-dose groups, respectively.

Investigators presented Phase II trial data for GVAX at ASCO 2002: the data showed a dose-dependent trend toward prolonged survival and longer median time to disease progression. Thirty-four patients with hormone-refractory CaP and metastatic bone disease received one of two dosing regimens of GVAX. Twenty-four patients received an initial dose of GVAX (500-million-cell prime dose) followed by 12 booster doses of 100 million cells each at two-week intervals; ten patients received the same prime dose followed by treatment with a higher dose of 300 million cells at the same intervals. At two-year follow-up, 9 of the 22 lower-dose-arm patients were alive (41%; 2 were lost to follow-up). By contrast, 7 of the 10 higher-dose-arm patients (70%) were alive at two-year follow-up. Investigators reported no dose-limiting or autoimmune toxicities. In September 2002, the company reported final data from this trial: the combined median survival for both dose groups was 26.2 months. A potential survival benefit requires confirmation in a Phase III trial, but the available data compare favorably with the median survival of 18.9 months achieved by docetaxel / prednisone in the same setting.

In 2002, at the Targeted Therapies First International Congress, Cell Genesys reported data from a small trial in the hormone-naive setting. Some patients experienced a reduction in PSA and bone lesions. Researchers also observed a dose-response trend in terms of overall survival.

On the basis of the encouraging dose-related response data reported in the Phase II trial of GVAX, Cell Genesys initiated clinical evaluation (Phase I / II) of a second-generation, high-potency GVAX vaccine in patients with hormone-refractory CaP and metastatic bone disease. This second-generation agent secretes GM-CSF at five- to tenfold higher levels than its predecessor. Treatment involves one of two doses of the vaccine (100 or 200 million cells) injected monthly for six months.

GVAX’s limitations include its failure to achieve an immune response in all patients and the need for intradermal or subcutaneous injection, which can cause local injection-site inflammation.