Oregovomab Plus Chemotherapy in Neo-adjuvant Setting in Newly Diagnosed Patients With Advanced Epithelial Ovarian Cancer

A Phase 2, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial Comparing Chemoimmunotherapy (Paclitaxel-Carboplatin-Oregovomab) Versus Chemotherapy (Paclitaxel-Carboplatin-Placebo) as Neoadjuvant Therapy in Patients With Advanced Epithelial Ovarian, Fallopian Tube or Peritoneal Carcinoma

A clinical study to compare the efficacy and safety of five administrations of oregovomab versus placebo, infused in schedule dependent sequence with specific cycles of a standard six-cycle chemotherapy regimen (paclitaxel and carboplatin), for the treatment of patients with newly diagnosed advanced ovarian cancer who are planned to receive neoadjuvant treatment followed by interval debulking surgery (IDS) and adjuvant treatment.

Phase 2, double-blind, placebo-controlled, multi-center study to compare the efficacy and safety of five administrations of oregovomab 2 mg IV versus placebo, infused in a schedule dependent sequence with specific cycles of a standard six-cycle chemotherapy regimen (paclitaxel and carboplatin), for the treatment of patients with newly diagnosed advanced ovarian cancer who are planned to receive neoadjuvant treatment. Patients will receive oregovomab or placebo at Cycles 1 and 3 in combination with paclitaxel and carboplatin prior to IDS, followed by oregovomab or placebo at Cycles 4 and 6 in combination with paclitaxel and carboplatin, and oregovomab or placebo monotherapy at Cycle 6 plus 12 weeks.

This study will screen approximately 96 patients to randomize approximately 88 patients. All eligible patients will be stratified by FIGO Stage (Stages IIIA, IIIB versus Stages IIIC, IV).

The study includes screening period, treatment period, post-treatment follow up, safety follow and long term follow up.

Inclusion Criteria:

1. Adult females 18 years old or older.

2. Newly diagnosed epithelial adenocarcinoma of ovarian, fallopian tube or peritoneal origin FIGO Stage III or IV patients whose disease is confirmed based on biopsy sample.

3. Eligible histologic epithelial cell types: high grade serous adenocarcinoma, high grade endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma not otherwise specified (N.O.S.).

4. Suitable venous access for the study-required procedures.

5. Serum CA125 levels ≥ 50 U/mL prior to Cycle 1 of NACT chemotherapy + oregovomab or placebo.

6. Adequate bone marrow function:

   1. Absolute neutrophil count (ANC) ≥ 1,500/μL.
   2. Platelets ≥100,000/μL.
   3. Hemoglobin ≥ 8.0 g/dL (Note: Blood transfusion is permitted up to 48 hours before the first dose of study treatment).

7. Adequate liver function:

   1. Bilirubin < 1.5 times upper limit normal (ULN).
   2. SGOT/AST and SGPT/ALT < 2.5 times ULN.

8. Adequate renal function:

   a. Creatinine ≤ 1.5 times ULN.

9. ECOG Performance Status of 0, 1 or 2.

10. Women of childbearing potential must be willing to avoid pregnancy by using a highly effective method of contraception from the first dose of study treatment to 6 months after last dose of study treatment.

11. Signed written informed consent form and authorization permitting release of personal health information. Ability to comply with treatment and follow up

Exclusion Criteria:

1. Patients with mucinous adenocarcinoma, carcinosarcoma, tumors with neuroendocrine features and low-grade adenocarcinoma (including low grade serous and FIGO grade 1 endometrioid adenocarcinomas of the ovary).

2. FIGO Stage IV patients:

   1. FIGO stage IV patients suspected or diagnosed with bone or brain metastasis are excluded.
   2. FIGO stage IV patients diagnosed with lung and/or liver metastasis with tumour size more than 2 cm are excluded.
   3. FIGO stage IV patients diagnosed with lung and/or liver metastasis and expected to administer with more than 3 cycles of chemotherapy and/or not suitable for interval debulking surgery are excluded.

3. Patients must not have received any prior chemotherapy, immunotherapy, targeted or hormonal therapy.

4. Patients who are lactating and breastfeeding or have a positive serum pregnancy test within 14 days prior to the first dose of study treatment.

5. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study treatment according to this protocol.

6. Active autoimmune disease such as rheumatoid arthritis, SLE, ulcerative colitis, Crohn's Disease, MS, or ankylosing spondylitis, requiring active disease modifying treatment.

7. Known allergy to murine proteins or hypersensitivity to any of the excipients of the oregovomab, paclitaxel, or carboplatin.

8. Chronically treated with immunosuppressive drugs such as cyclosporine, adrenocorticotropic hormone (ACTH), etc.

9. Chronic therapeutic corticosteroid use, defined as > 5 days of prednisone or equivalent, except for inhalers or those on a pre-planned steroid taper. (Note: Premedication with corticosteroids per institutional standard of care is allowed.)

10. Recognized acquired, hereditary, or congenital immunodeficiency disease, including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia.

11. Clinically significant active infection(s) at the time of screening.

12. Any of the following conditions (on-study testing is not required):

    1. Known HIV-infected patients unless on effective anti-retroviral therapy with an undetectable viral load within 6 months prior to randomization, or
    2. Known or suspected hepatitis B if active infection (patients with chronic hepatitis B infection must have an undetectable HBV viral load on suppressive therapy, if indicated; positive surface antibody alone is not an exclusion), or
    3. Known or suspected hepatitis C infection which has not been treated and cured unless currently on treatment with an undetectable viral load.

13. Uncontrolled or life-threatening diseases compromising safety evaluation. Diagnosed or treated for another malignancy within 5 years before the first dose, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer, ductal carcinoma in-situ (DCIS) of the breast or cervix carcinoma in situ are not excluded if they have undergone complete resection. a. Synchronous endometrial cancer, but a prior diagnosis of endometrial cancer within 5 years is not excluded if all of the following conditions are met: Stage IA, superficial myometrial invasion, without lymphovascular invasion, and not poorly differentiated subtypes including papillary serous, clear cell or other FIGO Grade II and III lesions.

15. Contraindication to the use of pressor agents. 16. Undergone prior surgical debulking. 17. History or evidence upon physical examination of CNS disease, seizures not controlled with standard medical therapy, or any brain metastases. 18. Any of the following cardiovascular conditions:

1. Acute myocardial infarction within 6 months before the first dose of study treatment.
2. Current history of New York Heart Association (NYHA) Class III or IV heart failure
3. Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic clinically significant findings. 19. Unable to read or understand or unable to sign the necessary written consent before starting treatment. 20. May not receive any live, attenuated vaccine administered within 28 days (or 4 weeks) prior to enrollment, during the study, and for at least 90 days after the last dose of study treatment. 21. Patients who will receive Hyperthermic Intraperitoneal Chemotherapy (HIPEC), any other anti-cancer medications, including bevacizumab, PARPi, or any other investigational agent(s) with 3 cycles of paclitaxel and carboplatin neo-adjuvant treatment will be excluded.