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Randomized, Placebo-Controlled Study of Oregovamab for Consolidation of Clinical Remission in Patients With Advanced Ovarian Cancer

Posted on: Friday, 5 August 2005, 09:00 CDT

Objectives

To evaluate oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study.

Introduction

Ovarian cancer is the leading cause of death from gynecologic malignancy. Despite high initial rates of response to surgery and platinum-based chemotherapy, high numbers of patients will relapse. There has been a consistent interest in additional therapy after clinical complete response that might delay or prevent recurrent of disease. Development of additional therapies that can complement standard front-line therapy in an effective but minimally toxic fashion are needed. Oregovomab is an immunotherapeutic agent used for immunotherapy in patients with adenocarcinoma of the ovary expressing the tumor-associated antigen, CA-125. Oregovomab acts as an immunotherapeutic agent by complexing with CA-125 and altering CA- 125 antigen processing. The resulting induction of cellular immunity has shown to be associated with a survival benefit. This study evaluated oregovomab as a potential consolidation therapy for ovarian cancer.

Methods

Patients with Stage III/IV ovarian cancer who had a complete clinical response to primary therapy were randomized to oregovomab or placebo administered at weeks O, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary endpoint was time to relapse (TTR).

Results

* Patients with stage III/IV epithelial ovarian cancer were treated with oregovomab (n=73) or placebo (n = 72).

* Time to relapse (TTR) was no different between oregovomab (13.3 months) and placebo (10.3 months).

Patient subgroup with successful front-line therapy (SFLT) defined as residual tumor ≤ 2 cm, CA-125 ≤ 65 U/ml before cycle 3 chemotherapy, no clinical evidence of disease after completion of front-line chemotherapy, and CA-125 < 35 U/ml at randomization into study showed following response:

* oregovomab TTR = 24 months

* placebo TTR= 10.8 months

* antibody response to oregovomab correlated with TTR.

Toxicity - most frequent toxicities asthenia, nausea, headache, pain:

* oregovomab group with 10/74 (13.5%) grade 3/4 toxicity

* placebo group 0% grade 3/4 toxicity.

Conclusion

Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to further determine whether the subgroup of SFLT patients derives a benefit from oregovomab treatment.

Selected references

1. Mobus VJ, Baum RP, et al. Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancer. Am J Obstet Gvnecol 2003; 189:28-36.

2. Berek JS, Schultes BC, et al. Biologic and Immunologie therapies for ovarian cancer. J CHn Oncol 2003;21:168s-74s.

Commentary

Patients with metastatic ovarian cancer are seldom cured by initial cytoreductive surgery and chemotherapy. The group of patients with a negative second-look surgery post front-line chemotherapy are thought to be most curable; however the recurrence rate in these negative second-look patients approaches 50%. The concept of consolidation therapy for ovarian cancer has been explored in multiple phase II and III trials seeking to improve survival and/or time to relapse by administration of additional therapy beyond front-line treatment. Evaluation of consolidation agents must weigh carefully the balance between efficacy and toxicity. In a SWOG phase II trial of oral altretamine administered for 6 months following first-line therapy, overall median progression free survival was 28 months and 48 months in those with optimally debulked disease. Toxicity was minimal. This approach is appealing because of ease of oral administration. Phase III trials of topotecan and taxol consolidation have also been reported. In the Italian group topotecan trial, no benefit was seen and grade 3/4 toxicity occurred in 58% of patients. In the GOG trial evaluating 3 versus 12 months of consolidation taxol, 12 months of monthly taxol demonstrated an improved progression-free survival. Toxicity was significant with 24% of patients experiencing grade 2/3 neuropathy. Despite the patient benefits, the authors of the GOG trial admit that a new standard of care for consolidation therapy is still yet to be established.

This trial evaluating monoclonal antibody therapy directed against the CA-125 antigen showed no benefit to the general population of ovarian cancer patients completing first-line therapy. Interestingly, the subpopulation of patients identified with the most optimal cytoreductive surgery and response to front-line chemotherapy did show a benefit from consolidation immunotherapy. Identifying the group of patients most likely to benefit from therapy is an important step in development of a new treatment. As stated by the authors, treating patients with oregovomab in their current phase III trial who demonstrated the most successful front- line therapy may truly determine the utility of oregovomab immunotherapy. The low toxicity and relative ease of administration make this an appealing therapeutic option.

Further reading

Alberts DS, et al. Long-term follow-up of a phase II trial of oral altretamine for consolidation of clinical response remission in women with stage III ovarian cancer in the Southwest Oncology Group. Int J Gynecol Cancer 2004; 14:224-8.

De Placido S, et al. Topotecan compared with no therapy after response to surgery carboplatin/paclitaxel in patients with ovarian cancer: Multicen Italian Trials in Ovarian Cancer (MITO-I) randomized study. J CHn Oncol 2004; 22:2635-42.

Markman M, et al. Phase III randomized trial of 12 versus 3 months of maintainance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trail. J CHn Oncol 2003;21:2460-5.

Berek JS, Taylor PT, et al. J Clin Oncol 2004;22:3507-16

Commentary by: David L. Tait, MD, Division of Gynecologic Oncology, Carolinas Medical Center, Charlotte, NC, USA

Copyright CRC Press Mar 2005

Source: Women's Oncology Review

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