GVAX® Plus Ipilimumab Provides Positive Results in Hormone-Refractory Prostate Cancer
Researchers from Amsterdam have reported further encouraging results with the treatment combination consisting of GVAX and ipilimumab (MDX-010) for the treatment of hormone-refractory prostate cancer (HRPC). These updated results from a Phase I study were presented at the 2007 annual meeting of the American Society of Clinical Oncology (ASCO) in June. Preliminary results of this study were presented at the 2006 ASCO meeting (see related news).
There remains a need for effective and well tolerated treatment choices for men with HRPC. GVAX is an immunotherapeutic agent comprising whole tumor cells that include the two genetically modified, non patient-specific prostate cancer cell lines LNCap and PC-3. These cell lines contain many common antigens found in metastatic prostate cancer. The cells have been modified to secrete granulocyte macrophage colony stimulating factor (GM-CSF) to stimulate a systemic immune response to the antigens used in the cell lines.
GVAX is administered intradermally on an outpatient basis. It is intended to be marketed for “off the shelf” pharmaceutical use in men with HRPC. GVAX is currently being evaluated in two Phase III trials, VITAL-1 and VITAL-2, and has recently received fast-track designation by the United States Food and Drug Administration (FDA).
Ipilimumab is a fully human antibody that is targeted against the CTLA-4. CTLA-4 is a molecule present on T-cells that is thought to play a role in suppressing the body’s immune response. Ipilumumab is being evaluated in several ongoing clinical trials for various types of cancers, including two registrational studies under two Special Protocol Assessment (SPA) agreements with the FDA for second-line therapy in metastatic melanoma.
The recent Phase I trial evaluating dose-escalation of the combination of GVAX and ipilimumab included 12 patients with HRPC. Six of these patients were treated at the doses that proved to provide optimal results (3 and 5 mg) and are being used in the Phase III trials evaluating each agent separately.
Of the 6 patients receiving optimal doses of therapy, 5 patients achieved at least a 50% reduction in prostate specific antigen (PSA) levels that lasted at least 2 months; 2 of these patients had a 95% reduction in PSA levels. 2 responses are still ongoing with a median 18 month follow-up.
Importantly, 3 of the 5 PSA responders demonstrated antitumor activity through improvement of multiple bone lesions as determined by bone scan, improvement of pain cause by bone metastases, and resolution of abdominal lymph node disease as determined by computed tomography (CT) scan. One patient had complete resolution of disease by CT scan.Sixty-six percent of the remaining patients who received GVAX plus lower doses of ipilimumab achieved disease stabilization as determined through PSA levels for at least two months.
* The main new finding in this study was that 5 of the 6 patients at the higher dose developed adrenal insufficiency and/or hypothyroidism requiring treatment.
* Other side effects occurring in more than 50% included fever, fatigue and anorexia.
* There was a clear association between adverse events and PSA responses.
* Multiple anti-tumor antibodies were identified by serology and biopsies showed T cell infiltration.
The researchers concluded that the treatment combination including GVAX and ipilimumab appears promising in the treatment of HRPC. Future larger trials evaluating this combination and comparing it to other treatment options will help determine its true clinical utility for men with HRPC.
Reference: Gerritsen W, Van Den Eertwegh A, De Gruijl T, et al. Biochemical and immunologic correlates of clinical responses in a combination trial of the GM-CAS-gene transduced allogeneic prostate cancer immunotherapy and ipilimumab in patients with metastatic hormone-refractory prostate cancer (MHRPC). Proceedings from the 43rd annual meeting of the American Society of Clinical Oncology. Chicago, IL. 2007. Abstract #5120.
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