Trial Information

Phase 2: A Randomized Controlled Study on Effectiveness of Chemotherapy (Carboplatin-Paclitaxel) Versus Chemo-immunotherapy (Carboplatin-Paclitaxel-Oregovomab) in Patients With Advanced Epithelial Ovarian, Adnexal or Peritoneal Carcinoma

It is estimated that new cases of ovarian cancer in the US for 2012 will be approximately
22,280 and the estimated deaths will be approximately 15,500 The five year survival rate
for ovarian cancer is approximately 40%. More than half of those diagnosed with ovarian
cancer have advanced disease. Although complete responses are common following initial
treatment with platinum and taxane regimens, within two years of cytoreductive surgery for
Stage III/IV disease, one-half of tumors recur. Once the patient relapses there is no
curative therapy. Recurrent ovarian cancer is invariably fatal. Thus, there is a need for
new therapies that will reduce the rates of recurrence and prolong the relapse-free
intervals.

Oregovomab is an investigational drug previously used in clinical trials as an
immunotherapeutic treatment of ovarian cancer patients whose tumor cells express the tumor
associated antigen, CA125. The active component of oregovomab is the activated murine
monoclonal antibody B43.13, an IgG1k subclass immunoglobulin that binds with high affinity
(1.16E10/M) to CA125.

CA125 is a surface glycoprotein antigen that is expressed on more than 80% of all
non-mucinous epithelial ovarian carcinomas where it occurs at elevated levels in the serum
of patients with ovarian cancer. Little is known about its biological function. CA125 is
associated with a large molecular weight mucin-like glycoprotein complex of 200-250 kDa and
its genetic structure has recently been elucidated. There is good evidence to suggest that
CA125 is a relevant target antigen for antigen-mediated immunotherapy of ovarian cancer.

Immunotherapy as a therapeutic approach to the treatment of cancer has recently been
established using several approaches. Sipuleucel T uses autologous PBMC's as a source of
antigen presenting cells to load patient cells with a prostate cancer tumor antigen to
induce cellular immunity directed against prostate cancer. With the recent approval of this
approach by FDA for advanced prostate cancer based on controlled survival data demonstrates
that induction of cellular immunity can bring benefit to cancer patients. The recent
success of ipilimumab in prolonging survival in melanoma patients using an antibody that
delays down regulation of specific immune responses further supports the rationale that
induction of specific T cell immunity to cancer is a viable therapeutic approach. To date no
successful immunotherapeutic approach has been established for ovarian cancer, and recurrent
advanced ovarian cancer remains an incurable disease.

Oregovomab, when dosed at 2 mg, has been demonstrated to induce cross presentation of CA125
peptide fragments and induce a CA125 specific cellular immune response. Most clinical
trials with oregovomab have been conducted in the maintenance setting where chemotherapy is
not being administered and the magnitude of response in this clinical setting has proven
inadequate to produce clinical benefit. Several reports, however, have suggested that
administration of oregovomab in association with chemotherapy may result in enhanced
cellular immunity relative to the monotherapy settings.

In 2009, a randomized phase 2 study was conducted in which simultaneous oregovomab and
standard chemotherapy was administered in a first group of patients and oregovomab was
administered a week after chemotherapy in a second group. The study showed that the arm
subjected to simultaneous immuno-chemotherapy developed a better immune response (contrary
to what was previously thought considering the immunosuppressive effects of chemotherapy).
Further studies, however, are needed to completely assess the magnitude of the immune
response. The measure of effectiveness of an immunotherapy in the treatment of cancer has
been fraught with the inability to successfully measure the direct effect on tumor burden
similar to cytotoxic therapies. We therefore believe in the importance of assessing not only
the rate of positivity obtained by ELISPOT method but also to verify safety, tolerability,
intradermal and antibody response, to assess the eventual delayed hypersensitivity (DTH)
against oregovomab, disease-free survival, and overall survival (up to the date fixed as the
last visit to complete the entire population evaluation). In a maintenance protocol with
oregovomab, only 10% of patients undergoing oregovomab treatment developed a positive
response in the ELISPOT assay performed without in vitro stimulation. In the 2009 Phase 2
trial, 42% of patients in the simultaneous infusion arm and 22% of patients in the one-week
delay arm had a positive ELISPOT response. Considering that the effect in a more optimal
population should be equal or greater than that obtained previously, we assume that 50% of
the study population in the chemoimmunotherapy arm should develop a positive response to the
ELISPOT assay in our protocol. We assume that the positive value of CA125 in patients
enrolled in this trial should provide a good level of immunity against this specific
glycoprotein in the arm undergoing chemo-immunotherapy. This study will evaluate the immune
response obtained by administration of oregovomab and how it's correlated with clinical
outcomes.