Comparing Paclitaxel-Carboplatin-Oregovomab versus Paclitaxel-Carboplatin-Placebo in Patients with Advanced Ovarian Cancer

Prior treatment

• BRCA1 or BRCA2 germline gene mutation test result with: a. Pathogenic, ambiguous or inconclusive result available within 28 days prior to starting study treatment. Subjects with BRCA1 or BRCA2 variants of uncertain significance can enroll onto the study as long as there is no intent to administer PARP inhibitors for front-line maintenance therapy, or b. Known BRCA1 and BRCA2 somatic mutations, if testing is performed
• Any of the following conditions (on-study testing is not required unless it is required by a specific participating country): a. Known HIV-infected subjects unless on effective anti-retroviral therapy with an undetectable viral load within 6 months, or b. Known or suspected hepatitis B if active infection (subjects 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 c. Known or suspected hepatitis C infection which has not been treated and cured unless currently on treatment with an undetectable viral load).
• 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, including ductal carcinoma in situ of the breast. Subjects with non-melanoma skin cancer, other carcinoma in situ if have undergone complete resection or cervix carcinoma in situ are not excluded if they have undergone complete resection. Synchronous endometrial and 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 lesions.
• Undergone more than one surgical debulking or have not recovered from surgery.
• Anticipated treatment with any other anti-cancer medications, including bevacizumab, PARP inhibitors, or any investigational agent(s) during the study.
• Any of the following cardiovascular conditions: a. Acute myocardial infarction within 6 months before the first dose of study treatment. b. Current history of New York Heart Association (NYHA) Class III or IV heart failure (see Appendix H). c. Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic clinically significant findings
• Known Somatic Homologous Recombination Deficiency (HRD) who will receive PARP inhibitor front-line maintenance therapy. Subjects with somatic HRD are eligible as long as there is no intent to administer PARP inhibitor front-line maintenance therapy.
• May not receive any live, attenuated vaccine administered within 28 days (or 4 weeks) prior to enrolment, during the study, and for at least 90 days after the last dose of study treatment.
• Subjects who receive Hyperthermic Intraperitoneal Chemotherapy (HIPEC), any other anti-cancer medications, including bevacizumab, PARP inhibitors, or any other investigational agent(s) with 3 cycles of paclitaxel and carboplatin neo-adjuvant treatment prior to IDS will be excluded.
• Chronically treated with immunosuppressive drugs such as cyclosporine, adrenocorticotropic hormone (ACTH), etc.
• Chronic therapeutic corticosteroid use, defined as > 5 days of prednisone or equivalent, with the exception of inhalers or those on a pre-planned steroid taper. (Note: Premedication with corticosteroids per institutional standard of care is allowed.)

Other illness

• Recognized acquired, hereditary, or congenital immunodeficiency disease, including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia.
• Clinically significant active infection(s) at the time of screening.
• Uncontrolled or life-threatening diseases compromising safety evaluation.
• History or evidence upon physical examination of CNS disease, seizures not controlled with standard medical therapy, or any brain metastases.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Active autoimmune disease, such as rheumatoid arthritis, SLE, ulcerative colitis, Crohn's Disease, MS, or ankylosing spondylitis requiring active disease modifying treatment.
• Known allergy to murine proteins or hypersensitivity to any of the excipients of the oregovomab, paclitaxel, or carboplatin.

Lab values

• Female subjects who are lactating and breastfeeding, orbreastfeeding or have a positive serum pregnancy test within 7 days prior to the first dose of study treatment (C1D1 for Cohort 1 or C4D1 for Cohort 2).

Other

• Contraindications to the use of pressor agents.
• Unable to read or understand or unable to sign the necessary written consent before starting treatment.
• Subjects with mucinous adenocarcinoma, carcinosarcoma, tumors with neuroendocrine features and low-grade adenocarcinoma.

• Adults 18 years old or older
• Adequate renal function: a. Creatinine ≤ 1.5 times ULN
• ECOG Performance Status of 0 or 1
• For 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. Adequate contraception is defined in Section 8.2.5. (Belgium and South Korea Only: Use of a highly effective method of contraception from 28 days before first dose).
• Signed informed consent and authorization permitting release of personal health information.
• Willingness and ability to complete patient quality of life questionnaires.
• Subjects with newly diagnosed epithelial adenocarcinoma of ovarian, fallopian tube or peritoneal origin FIGO Stage III or IV disease.
• 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.).
• Completed debulking surgery (either primary debulking surgery or interval debulking surgery at the discretion of the investigator), as defined below: a. For subjects who undergo primary debulking surgery (Cohort 1 - Primary Surgery): i. Subject must receive initial dose of paclitaxel 175 mg/m2 given intravenously, and carboplatin AUC 6 IV every 3 weeks (21 days) for 6 cycles. Carboplatin total dose given as 5 consecutive daily pulse doses, for subjects who experiences significant grade 3 or higher emesis. Subsequent dose modifications will be instituted per protocol. Cycle 1 of chemotherapy ± oregovomab/placebo must be anticipated to occur within 6 weeks after primary debulking surgery, and ii. The primary debulking surgery is optimal, R1 or R0 (defined as R1, macroscopic less than 1 cm in diameter, or R0, microscopic or no evidence of tumor). Assessment of intra-abdominal optimal debulking will be determined at the time of the surgical procedure and not by postsurgical imaging (i.e., CT scan). Assessment of intra-abdominal optimal debulking will be determined at the time of the surgical procedure and not by post-surgical imaging (i.e., CT scan). b. For subjects who will undergo interval debulking surgery (IDS) (Cohort 2 – NACT+/Interval Surgery): i. Prior to IDS, subject must have received neoadjuvant treatment with 3cycles of paclitaxel and carboplatin a) paclitaxel must have been started at an initial dose of 175 mg/m2 given intravenously (IV) every 3 weeks (21 Days) ). If the subject experienced grade 3 or 4 adverse events with paclitaxel 175mg/m2, dose reduction to 135 mg/m2 is allowed for cycles 2 and/or 3. b) Carboplatin initial dose must have been an area under the curve (AUC) 5-6 IV approximately every 3 weeks (21 Days) ii. Once subjects are enrolled on the protocol, they must receive paclitaxel 175mg/m2 IV and carboplatin AUC 5-6 IV every 3 weeks starting cycle 4. Subsequent dose modifications will be instituted per protocol. Cycle 4 of chemotherapy ± oregovomab/placebo must be anticipated to occur within 6 weeks after interval debulking surgery, and iii. The interval debulking surgery is optimal, R1 or R0 (defined as R1, macroscopic less than 1 cm in diameter, or R0, microscopic or no evidence of tumor). Assessment of optimal debulking of intra-abdominal disease will be determined at the time of the surgical procedure and not by post-surgical imaging (i.e., CT scan).
• Suitable venous access for the study-required procedures.
• CA 125 levels: a) Cohort 1 – Primary Surgery: Preoperative serum CA-125 levels ≥ 50 U/mL, or b) Cohort 2 – NACT + Interval Surgery: serum CA-125 levels ≥ 50 U/mL prior to first neoadjuvant chemotherapy.
• Adequate bone marrow function: a. Absolute neutrophil count (ANC) ≥ 1,500/μL b. Platelets ≥ 100,000/μL
• Hemoglobin ≥ 8.0 g/dL (Note: Blood transfusion is permitted up to 48 hours before first dose of study treatment).
• Adequate liver function: a. Bilirubin < 1.5 times upper limit of normal (ULN) b. Lactate Dehydrogenase (LDH), SGOT/AST and SGPT/ALT < 2.5 times ULN