A Controlled Study of the Effectiveness of Oregovomab (Antibody) Plus Chemotherapy in Advanced Ovarian Cancer

• Time to clinical relapse [ Time Frame: Study termination (approxmiately 25 weeks after Cycle 1) ] [ Designated as safety issue: No ]
  The time period from the date of randomization to the date of confirmed relapse as defined by clinical, radiologic, and/or pathologic evaluations.
• Immune parameters: HAMA (human anti-mouse antibody) titers and DTH (delayed type hypersensitivity) [ Time Frame: HAMA: screening, Cycle 3 (approx. 6 weeks after Cycle 1), Cycle 5 (approx. 12 weeks after Cycle 1), Cycle 5 plus 12 weeks (approx. 24 weeks after Cycle 1) DTH: screening and termination (approx. 25 weeks after Cycle 1) ] [ Designated as safety issue: No ]
  Laboratory test for (HAMA) human anti-mouse antibody present in patients' sera. DTH (delayed type hypersensitivity) is an on-site test conducted by the investigator by injecting a small amount of the Oregovomab product and three other antigens (mumps, tetanus, and Candida) into the skin of the patient and observing the effects.
• Clinical response [ Time Frame: Up to three years after enrollment in the study ] [ Designated as safety issue: No ]
  Patients will be categorized into one of the following: increasing disease, stable disease, or progression [measurable disease studies]
• Survival [ Time Frame: Up to three years after enrollment in the study ] [ Designated as safety issue: No ]
  The observed length of life from entry into the study to death or the date of last contact
• Change in vital signs from baseline to end of study [ Time Frame: At Baseline (up to 4 weeks before Cycle 1), Cycle 3 (approximately 6 weeks after Cycle 1), Cycle 5 (approximately 12 weeks after Cycle 1) and Cycle 5 plus 12 weeks (approxmately 24 weeks after Cycle 1) ] [ Designated as safety issue: Yes ]
  The following vital signs will be obtained: heart rate, respiratory rate, blood pressure, temperature
• Change in clinical laboratory results from baseline to end of chemotherapy [ Time Frame: At Baseline (up to 4 weeks before Cycle 1), Cycle 3 (approximately 6 weeks after Cycle 1), Cycle 5 (approximately 12 weeks after Cycle 1), Cycle 5 plus 12 weeks (approxmately 24 weeks after Cycle 1) and termination (approximately 25 weeks after Cycle 1) ] [ Designated as safety issue: Yes ]
  The following clinical laboratory results will be obtained: hematology (White Blood Cells [total count and differential], hemoglobin, hematocrit, Red Blood Cells), biochemistry (albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin [total], lactate dehydrogenase, protein, creatinine, urea, bicarbonate, chloride, potassium, sodium, calcium, phosphate, glucose, uric acid) and urinalysis (dipstick, pH, specific gravity, bilirubin, blood, protein, glucose, ketones, urobilinogen, microscopic evaluation)

This is a Phase 2 randomized study with two treatment arms to compare the effectiveness of oregovomab (a murine monoclonal antibody directed against CA125) when combined with first-line chemotherapy (carboplatin and paclitaxel) to first-line chemotherapy (carboplatin and paclitaxel) alone in female patients with advanced ovarian cancer. This study is to confirm previous results that showed oregovomab was able to help the body to produce an immune response to CA125 (a target that has been identified on ovarian cancer cells) in patients with stage III-IV ovarian cancer when they were receiving chemotherapy for their disease. The primary aim of the study is to see how well these patients with advanced ovarian cancer make an immune response to CA125 by using a specific test (ELISPOT assay) of the patient's blood. The study will also look at the side effects of the oregovomab, other immune response parameters, how well the patients respond to the treatment of their disease (how long it takes to show that their disease has progressed and how long these patients survive overall).

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.

• Drug: Carboplatin & paclitaxel
  Carboplatin (AUC 6, administered intravenously in a single day for 6 cycles every three weeks [21 days])plus paclitaxel (175 mg / square meter, intravenously over three hours in one day to be repeated for 6 cycles every three weeks [21 days])
  Other Names:

  • Abraxane
  • Paclitaxel
  • Carboplatin
• Biological: Carboplatin & paclitaxel & oregovomab
  Carboplatin (AUC 6, administered intravenously in a single day for 6 cycles every three weeks [21 days]) plus paclitaxel (175 mg / square meter, intravenously over three hours in one day to be repeated for 6 cycles every three weeks [21 days]) plus oregovomab (2 mg infused intravenously jointly during the 1st, 3rd and 5th chemotherapy cycle and 12 weeks after the 5th cycle).
  Other Names:

  • Abraxane
  • Palictaxel
  • Carboplatin
  • Oregovomab

• Active Comparator: Carboplatin & paclitaxel
  first-line chemotherapy for ovarian cancer
  Intervention: Drug: Carboplatin & paclitaxel
• Experimental: Carboplatin & paclitaxel & oregovomab
  first-line chemotherapy for ovarian cancer plus oregovomab
  Intervention: Biological: Carboplatin & paclitaxel & oregovomab

Inclusion Criteria:

• have newly diagnosed epithelial adenocarcinoma of ovarian, tubal or peritoneal origin and FIGO Stage III/IV disease.
• have preoperative CA125 levels > 50 U/mL
• have optimal cytoreduction (RT=0)
• be anticipated to have first-line chemotherapy infusion within 6 weeks after surgery
• be available to complete the protocol for the duration of the study
• have adequate Bone marrow function: Absolute neutrophil count (ANC) greater than or equal to 1,500/µL, equivalent to Common Terminology Criteria (CTCAE v3.0) grade 1. Platelets greater than or equal to 100,000/µL; hemoglobin greater than or equal to 8.0 g/dL
• have adequate Renal function: creatinine less than or equal to 1.5 x institutional upper limit normal (ULN), CTCAE v3.0 grade 1
• have adequate Hepatic function: bilirubin less than or equal to 1.5 x ULN (CTCAE v3.0 grade 1). SGOT and alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE v3.0 grade 1)
• able to sign informed consent and provide authorization permitting release of personal health information
• have an ECOG Performance Status of 0 or 1

Exclusion Criteria:

• have an active autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), ankylosing spondylitis)
• have a known allergy to murine proteins or have had a documented anaphylactic reaction to any drug, or cannot tolerate cyclophosphamide
• are being chronically treated with immunosuppressive drugs such as cyclosporin, adrenocorticotropic hormone (ACTH), or systemic corticosteroids.
• have a recognized immunodeficiency disease including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia
• have an acquired, hereditary, or congenital immunodeficiency
• have uncontrolled diseases other than cancer
• have contraindications to the use of pressor agents
• have undergone more than one surgical debulking
• have hepatic dysfunction, eg, bilirubin more than 1.5 times higher than normal levels, LDH, SGOT and SGPT doubled compared to normal or albumin <3.5 g/dL
• have severe renal insufficiency with serum creatinine >1.6 mg/dL
• have concomitant diseases or treatments that may confound the results of the study, which may preclude the completion of the protocol or may mask adverse reactions
• are to be tested with other medications during treatment
• are unable to read or understand or unable to sign the necessary written consent before starting treatment