GVAX for Prostate Cancer

GVAX for prostate cancer is Cell Genesys’ most promising and advanced-stage candidate. It is composed of two prostate cancer cell-lines that contain many common antigens found in metastatic prostate cancer. The need for better treatment for this deadly disease, which is the second leading cause of cancer death in men in the United States, is obvious, especially among patients with advanced-stage disease. GVAX is currently being evaluated in two phase III trials for the treatment of prostate cancer in its advanced (metastatic) stages, after patients cease to respond to hormone therapy and radiation. This state is referred to as metastatic Hormone Refractory Prostate Cancer (mHRPC) and is generally associated with poor prognosis. With a yearly death toll reaching 60,000 men in the US & Europe, the potential of an effective treatment that results in prolonged survival is huge.

Although very big, the market for mHRPC is awfully crowded, with many promising agents in clinical development, including numerous cancer vaccines (like Dendreon’s Provenge and Northwest’s DCVax-Prostate) and numerous promising chemotherapy agents. The most impressive performance was achieved by combining Taxotere and Celgene’s Thalidomide, which resulted in a median survival of 25.9 months compared with 14.7 months for the Taxotere alone arm in a phase II trial. Although in most clinical trials Taxotere achieved a median survival of 17-20 months, 25.9 months still represents a substantial improvement.

Cell Genesys has reported encouraging results from five clinical trials of GVAX for prostate cancer including two phase II trials.

The first phase II trial included 34 mHRPC patients, whose cancer had spread to the bones and other tissues. This patient population, which is usually treated with chemotherapy, was administered with GVAX for prostate cancer as their sole anti-cancer therapy. Originally, all of the 34 patients were supposed to receive the same dose of GVAX. However, since in the first 24 patients to be enrolled, no severe side effects were observed, researchers decided to administer a higher dose of GVAX to the remaining patients. Hence, the first group (24 patients) was administered with a low dose of GVAX for prostate cancer while the second group (10 patients) received a higher dose. Overall Median survival for the 34 patients came at 26.2 months, more than 6 months better than the historic figures achieved by Taxotere chemotherapy plus prednisone, the standard therapy for mHRPC. Furthermore, the median survival for the 10 patients who received the higher dose, which is currently being employed in the phase III trials, was an impressive 34.9 months.

Updated results from the more recent phase II trial were published this April. The trial enrolled 80 patients with metastatic HRPC who were split into three dose groups. The median survival for the 22 patients who were treated with a similar dose to the currently employed dose in the phase III trials was, again, 35 months.

The striking similarity in the survival of the two groups who received a dose similar to the one currently employed in the phase III, is an encouraging sign because consistent results are considered to be more reliable. Additionally, an obvious dose dependent effect was observed, since higher doses gave rise to better survival figures. A dose-dependent response should be one of the most important indications in assessing any drug’s activity. Even more encouraging is the fact that in both groups, the predicted survival was around 22 months. However, this data should not be regarded as anything but an indication due to the small number of patients and the lack of control groups. If such a survival improvement is achieved in one of the ongoing phase III trials, it will represent an impressive achievement for GVAX, both as a potential drug for prostate cancer and as a concept in general.

When patients in the phase II trials were evaluated for immunological response against prostate tumors, there was a broad response in the majority of patients against many prostate cancer antigens. These immunological responses were demonstrated by identification of antibodies and T lymphocytes directed against specific prostate tumor associated antigens. Interestingly, although the GVAX for prostate cancer is a non- patient-specific treatment, immune responses were predominantly patient-specific and unique from patient to patient. Hence, the GVAX cells, which are not identical to each patient’s cancer cells, manifested a personalized specific immune response within each patient’s body.

GVAX for prostate cancer is currently being evaluated in two multi-center, international phase III trials. Both trials are randomized, comparative and involve a substantial number of patients, 600 each. The first phase III clinical trial (VITAL-1) was initiated 3 years ago and compares GVAX to Taxotere + prednisone, for the treatment of metastatic HRPC in its early stages (Asymptomatic). Recruitment has just been completed with interim data expected to be released in the first half of 2008 and final data expected to be presented in 2009.

The second Phase III clinical trial (VITAL-2) commenced in 2005 and evaluates the combination of GVAX + Taxotere Vs. Taxotere + prednisone. This trial involves metastatic HRPC patients who have cancer-related pain and poorer survival prospects compared to the VITAL-1 patient population. A timeline for data release from this trial, which unfortunately will be of shorter duration due to poorer survival, has not been given yet.

Both trials are of high importance; however VITAL-2, where GVAX is combined with Taxotere, seems to be more intriguing. GVAX and Taxotere each belong to totally different subclasses of therapy. While GVAX is an immunotherapy treatment aimed at manifesting an immune response against tumors, Taxotere is a chemotherapy agent that indiscriminately prevents cells from multiplying and eventually leads to programmed cell death. The combination of chemotherapy and cancer vaccines is perceived to be problematic because chemotherapy’s alleged negative effect on the immune system. While chemotherapy agents inhibit cell growth and division, cancer vaccines are aimed at stimulating growth and division of immune cells. However, mounting evidence indicates that not only is it possible to combine Taxotere with cancer vaccines, this high- profile chemotherapy drug may actually exert beneficial effects on the immune response induced by cancer vaccines. Evidence includes clinical results from a phase II trial, which evaluated the combination of Taxotere with Therion’s virus-based cancer vaccine for mHRPC and trials evaluating GVAX for Melanoma in mice, which showed that Taxotere had a synergistic effect on the cancer vaccine’s ability to delay tumor growth.

Cell Genesys is also collaborating with Medarex in evaluating GVAX for mHRPC in combination with Ipilimumab (where do they come up with those names….), a monoclonal antibody that stimulates the immune system. Ipilimumab is expected to influence a wide variety of malignancies since it activates a group of immune cells called cytotoxic T lymphocytes (CTLs), rather than targeting cancer cells directly. In many cases, cancer cells can inhibit activation of CTLs by binding to a special receptor (CTLA4) presented by these highly critical immune cells. Ipilimumab was designed to bind the CTLA4 receptor and to prevent the inhibition of CTLs. Hence; the combination of the two drug candidates is very reasonable. In a phase I/II trial, GVAX was given to 12 patients in a dose level similar to that of the phase III trials in combination with 4 dose levels of Ipilimumab. PSA (Prostate-specific Antigen) declines of greater than 50% were observed in 5 out of the six patients who had received the two highest doses. These responses were maintained in four of these patients for at least six months. Just like the other phase II trials of GVAX as mono-therapy, there was clear evidence of immunologic stimulation like enhanced T cell activity and cancer-specific antibody production that occurred in a dose-dependent manner. Furthermore, each patient who responded to the treatment had a unique profile of cancer-related antibodies, an indication of a patient-specific response. Following these results, the two companies decided to recruit additional patients who will be given GVAX + Ipilimumab in the second highest dose (3mg/kg). The company expects more data from the trial will be published later this year

Targeting early stages in prostate cancer is another area Cell Genesys is evaluating for its GVAX for prostate cancer. In July of 2006, the company published results from a phase I/II trial, which included 21 early stage patients after surgical removal of all or part of the prostate gland. 16 patients showed a statistically significant decrease in the rate of rise of PSA (PSA slope) with one patient having a bigger than 50% reduction in PSA levels. In the patients who responded to GVAX, there was evidence of an immune response in the form of antibodies against prostate cancer-related antigens.

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