Study Summary
The study is a double-blind, placebo-controlled, parallel-group and randomized design. This Phase IIb, multicenter trial investigates the safety and efficacy of Anti-idiotype Induction Therapy (AITTM) with OvarexTM MAb-B43.13 compared with placebo for the treatment of women with metastatic ovarian cancer who have complete clinical response to surgery and cisplatin chemotherapy.

The death rate from ovarian cancer has remained unchanged over the past four decades. The 5-year survival rate for women diagnosed with regional disease is 41% and only 21% for those with distant disease. Although most patients initially respond to platinum or taxol chemotherapy , the relapse rate is approximatively 85% and at that stage there is no known curative therapy (1).

The novel form of immunotherapy associated with the administration of OvarexTM MAb-B43.13 is called Anti-idiotype Induction Therapy (AITTM). It consists of the injection of small amounts of specifically-treated murine antibodies which induce the immune system to produce human anti-murine antibodies (HAMA) in the form of autologous analogues [Ab(2)] of CA 125 against which the body elicits a strong immunologic response (2). CA 125 is a surface antigen that is expressed on more than 80% of epithelial ovarian carcinomas. Data from clinical trials to date indicated that the generation of an effective immune response to OvarexTM MAb-B43.13 results in a prolongation of patient survival.

A total of 212 patients will be randomly allocated to Treatment Group A or B (placebo). Patients assigned to Group A will receive an initial single intravenous injection of 2 mg of OvarexTM MAb B43.13 followed by 2 additional doses at intervals of 4 weeks. Thereafter, patient is eligible to receive at quaterly intervals a booster injection, if the patient has not experienced disease relapse, suffered from adverse effects and has HAMA level less than 100,000 ng/L.

The primary efficacy endpoint is to compare the time to disease relapse in both treatment groups and to monitor the safety of the treatment. The secondary variables will compare quality of life and length of survival and to evaluate patientsŐ immune response. Patients will remain in the hospital for one full hour following the injection of drug or placebo for any sign of anaphylaxis. Multiple doses of the adjuvant treatment can cause an allergic reaction which may be severe or life threatening. The development of HAMA to MAb-B43.13 will occur in virtually all patients.

References:

1. National Cancer Institute of Canada. Canada Cancer Statistics 1996.
2. Fagerberg J. et al. Cancer Immunol Immunother. 38:149-159, 1994.

Lay Summary
Ovarian cancer remains an extremely difficult tumor to cure, even though the initial response to chemotherapy, even for advanced disease, is very good. While current chemotherapy can result in dramatic shrinkage and even disappearance of tumor in a majority of cases, in most people it inevitably returns. Attempts to take advantage of the good initial response to chemotherapy have been made using a variety of approaches, including extremely high doses of additional chemotherapy with bone marrow transplantation.

This protocol takes a different approach. Antibodies have been developed which recognize CA-125, the protein that is made in most ovarian tumors, and often spills over into the blood stream. When the antibody recognizes and binds to this protein, it appears to stimulate an immune reaction against the tumor cells that make CA-125. In this way it functions as a vaccine. This may or may not result in a benefit to patients, and that is the question this trial is asking.

Patients whose tumor produces CA-125, whose tumor was not entirely removed at surgery, and whose tumor responded completely to chemotherapy are eligible. They are randomized to receive either placebo, which is comparable to the current standard approach of no further treatment, or the antibody. The antibody has some side-effects such as fever, chills, and the risk of a more intense allergic reaction. Patients are carefully monitored during and after treatment, and both groups are carefully followed to detect the status of the tumor.

Patient Eligibility
Patients with epithelial adenocarcinoma of ovarian, tubal or peritoneal origin who had clinical complete responses to their primary treatment (surgery and chemotherapy with cisplatin or carboplatin, either singly or in combination with other agents such as paclitaxel) are eligible for this study. Patients will be allocated to Treatment Group A or B within 6 weeks of completing primary chemotherapy.
Patients are eligible for enrollment into this study if they meet the following criteria:

1. Recently diagnosed patients who have histologically proven epithelial adenocarcinoma of ovarian, tubal, or peritoneal origin and their disease is classified as FIGO Stage III or IV.
   
2. Patients must have a performance status of < 2 on the ECOG scale or 60% on the Karnofsky scale.
   
3. Patients must have reached 18 years of age.
   
4. Patients must have an expected survival of at least 6 months.
   
5. Patients must have had an elevated CA 125 (>35 U/mL) measured prior to or at surgery (i.e. no later than the immediate post-Surgery period when the patient is in the surgical recovery room.) If a pre-surgical CA 125 measurement is not available, then the patient must have: (a) A serum CA 125 level >100 U/mL; and (b) tumor tissue which has been demonstrated by immunohistochemical methods to strongly express CA 125.
   
6. Patients must have residual disease that is either visible to or palpable by surgeon (i.e. must be residual positive) at the completion of the staging laparotomy procedure.
   
7. Patients must have had complete clinical response to their primary treatment protocol which includes laparotomy followed by platinum-based adjuvant chemotherapy. (A complete clinical response is defined as one in which the patient had a normal physical examination; no conclusive evidence of residual tumor by CT of the abdomen and pelvis, abnormal chest x-ray, and a normal serum CA 125 level (< 35 U/mL). Patients who had microscopic residual disease detected by laparoscopy are acceptable.
   Second look laparotomy (SLL) is permitted but is not a requirement of this study. SLL is defined as a laparotomy or laparoscopy in a patient in complete clinical, radiologic, and biochemical (CA125) remission. Patients undergoing SLL so defined are eligible even if disease is detected. A laparoscopy or laparotomy performed to confirm the presence of clinically or radiologically suspected disease will not qualify as SLL for purposes of this study and a finding of disease will render the patient ineligible.
   
8. Patients are eligible if they have undergone no more than one interval debulking procedure.