|Julia Draznin Maltzman, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
Ovarian cancer is typically treated with a combination of surgery and chemotherapy. Most cases of ovarian cancer are detected at an advanced stage due to limitations of current screening techniques and because it typically does not produce symptoms until an advanced stage. Although most ovarian cancers respond to our currently available treatments, many patients eventually experience a recurrence of their disease. Thus clinical trials exploring new avenues of treatment have been initiated. One of the new and exciting areas of research is the development of "targeted therapies" for a variety of cancers, including ovarian cancer.
A phase II study was released at the Gynecologic Oncology meeting last year, that promises some new hope and puts new energy and excitement into the field. Oregovomab (OvaRex, Unither Pharmaceuticals, Wellesley Hills, MA), a monoclonal antibody that targets CA 125, when given to women with advanced ovarian cancer following their surgery, successfully extended time to disease recurrence in a randomized, placebo-controlled, prospective study.
After initial surgery and chemotherapy, patients were randomized to receive the study drug, oregovomab, or placebo. Both were administered every four weeks until relapse or intolerance. The primary end point of the study was time to disease relapse. The outcome of surgery or response to upfront chemotherapy did not influence inclusion or exclusion.
Close to half of all participants had favorable characteristics: successful maximal surgical debulking, a good response to the first 2 cycles of chemotherapy as measured by CA-125, a normal CA-125 at the start of monoclonal antibody treatment, and absence of clinical disease. These favorable patients were later analyzed in a subset analysis to see if their performance differed from those women who did not have these favorable prognostic factors.
The treatment was very well tolerated. Using a questionnaire, researchers were able to show no difference between the study group participants and those taking placebo in terms of overall quality of life and general health. Most of the adverse events noted were mild - grade 1 or 2. The most common complaint was fatigue which was noted in 23% of the antibody treated women, and in 18% of the placebo treated group.
Induction of the immune system is measured by the development of the Human Anti-Mouse Antibodies (HAMA). A HAMA response is associated with a significant advantage in disease free survival, per study investigators. To begin with, the grouping of the monoclonal antibody (from a mouse) and the CA-125 protein functions as the foreign antigen against which the immune system is directed. The natural dendritic cells activate secondary and tertiary antibodies. All patients receiving the antibody had an increased response rate and this response was sustained for the duration of treatment. However, a sub-group analysis showed that progression-free survival was only observed in those patients who had optimal response to previous surgery and chemotherapy. In other words, those patients whose tumor was not maximally debulked during initial surgery, those whose tumors failed to decrease in CA-125 after chemotherapy, or those who had clinical disease at the onset of the study, did not experience a statistically significant prolongation in progression-free survival.
The median time to progression was 13.3 months with oregovomab and 10.3 months with placebo. In a subset analysis, the optimal group had a median time to relapse of 24 months.
Although the study was very well designed, there are some criticisms of this study. It was noted that accrual was discontinued early and the majority of the optimal patients ended up in the experimental arm. Most of the "less optimal" patients wound up in the placebo arm. This imbalance could bias the results of the trial. Another criticism pointed out that the immune response as measured by HAMA , and seen in patients receiving the antibody, may reflect the fact that these particular patients are more immunocompetent and thus may have a better outcome regardless of therapy. Although this is a distinct possibility, the only way to answer these questions is to perform a phase III clinical trial where survival is the end point.
Phase III trials called IM munotherapy Pivotal ovArian Cancer Trial I and II (IMPACT) are currently enrolling "optimal" patients with stage III - IV ovarian cancer after initial surgery and chemotherapy. The same drug administration schedule and dose as used in the Phase II trial are being used in these studies. These trials will examine the monoclonal antibody for possible "consolidation" therapy with the hope of translating response rates to actual survival benefits. The primary end points are disease-free survival, quality of life, and immune response.
If you are interested in looking for clinical trials for which you may be eligible please visit the OncoLink/EmergingMed clinical trials matching resource.