The use of oregovomab and PARP inhibitors in the treatment of ovarian cancer

Abstract

This document describes a method for improving the chances of survival of stage III-IV ovarian cancer patients. The method includes at least the steps of (a) administering a therapeutically effective amount of niraparib to stage III-IV ovarian cancer patients daily for at least 12 weeks, and (b) administering a therapeutically effective amount of monoclonal antibody mAb-B43.13 at week 1, week 4, week 7, week 12 and week 20 of the treatment period, where (a) is performed first and step (b) is performed second, thereby improving the chances of survival of the patients compared to control patients who are diagnosed with stage III-IV ovarian cancer and receive standard of care chemotherapy.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 USC § 119(e) to U.S. Provisional Patent Application No. 63 / 320,844, filed March 17, 2022, the specification of which is incorporated herein by reference in its entirety. [Technical field]

[0002] The disclosed subject matter relates generally to methods of improving the survival chances of stage III-IV ovarian cancer patients by administering a combination immunotherapy comprising a monoclonal antibody and a PARP inhibitor, more specifically, a combination of the monoclonal antibody mAb-B43.13 (oregovomab) and the PARP inhibitor niraparib. [Background technology]

[0003] (b) Relevant prior art Ovarian cancer is a malignant tumor of the ovary and is the second most common cancer of the reproductive organs after cervical cancer. The most common type of ovarian cancer is epithelial ovarian cancer, which occurs in the epithelial cells that cover the outer layer of the ovary, accounting for approximately 90% of all ovarian cancers. As there are no specific symptoms, more than 60% of cases are already at stage 3 or higher at the time of diagnosis, and many tend to occur simultaneously in both ovaries [Matsuo, K. et al. (2010); Hamanishi J., et al. (2015)]. The reality is that the cancer is highly likely to recur, as current ovarian cancer surgery or standard cytotoxic chemotherapy cannot completely cure the cancer. Ovarian cancer surgery aims to remove as many cancer cells as possible from the body, regardless of the stage of the disease, but ovarian cancer cells are small and metastasize quickly, making it difficult to completely remove them through surgery. In addition, currently used anticancer drugs cannot completely remove the cancer cells. Some ovarian cancer cells are resistant to anticancer drugs. As a result, some of them continue to grow even after chemotherapy, and many patients experience anticancer drug resistance or recurrence. In addition, targeted therapies developed to compensate for the limitations of cytotoxic anticancer drugs only delay recurrence by four months compared to standard anticancer drug treatment, and are limited in their ability to prevent frequent recurrences [Burger RA, et al. (2011); Perren TJ, et al. (2015)].

[0004] Oregovomab is a murine IgG1 monoclonal antibody (mAb) with a κ-light chain. It has a sub-nanometer binding affinity to cancer antigen 125 (CA-125) in the blood circulation. The therapeutic purpose of oregovomab administration is to play a key role in the recognition of CA-125 antigen by lymphocytes by antigen processing cells, especially dendritic cells (Figure 1). This is a similar mechanism to other anticancer vaccines [Berek J, et al. (2009)]. CA-125 is a large membrane glycoprotein known as mucin 16 or MUC16, and is encoded by the MUC16 gene. CA-125 is one of the known tumor-associated antigens (TAA) of ovarian cancer and is highly expressed on epithelial cancer cells. CA-125 is frequently detected in the blood of more than 80% of patients with epithelial ovarian cancer, and this tumor-associated antigen (CA-125) increases with the progression of the cancer. CA-125 is a proven tumor marker used to evaluate the efficacy of treatment and predict recurrence. In basic research using oregovomab, several studies have been conducted to characterize the induction of tumor-specific immunity. In a severe combined immunodeficiency mouse model bearing CA-125-expressing tumors, administration of oregovomab suppressed ascites production, reduced tumor size, and led to long-term survival. The most powerful biological mechanism of oregovomab is to activate T helper (Th)1 cells or cytotoxic T lymphocyte (CTL) cells by expressing CA-125 antigen on dendritic cells, thereby promoting anticancer effects against CA-125-overexpressing cancers. More than 90% of patients showed antibody responses to the immunoglobulin constant region of oregovomab, and antibody responses were also induced in the variable domain portion of oregovomab. Administration of oregovomab forms immune-antibody complexes (CA-125-oregovomab complexes) not only in peripheral tissues but also in the blood. The induction of this immune-antibody complex induces a therapeutic immune response [Brewer, M., et al. (2020)].

[0005] Poly(ADP-ribose) polymerases (PARPs), particularly PARP1 and 2, are Zn-finger deoxyribonucleic acid (DNA)-binding enzymes that play an important role in DNA repair (Fong et al. 2009). When DNA breaks are formed, PARPs bind to the ends of the broken DNA strands, and this process activates their enzymatic activity.

[0006] Activated PARP catalyzes the addition of long polymers of adenosine diphosphate (ADP)-ribose to PARP and several other proteins associated with chromatin, including histones and various DNA repair proteins (De Lorenzo et al. 2013, Jones et al. 2015). As a result, chromatin relaxes and DNA repair proteins are rapidly recruited, resulting in efficient repair of DNA breaks. Thus, PARP plays a key role in sensing DNA damage and transducing it into intracellular signals that activate base excision repair (BER) and single-strand break repair pathways.

[0007] Normal cells repair up to 10,000 DNA aberrations every day, with single-strand breaks being the most common form of DNA damage. Cells unable to repair such a load of DNA damage, such as those with defects in homologous recombination or the BER pathway, are at risk of accumulating multiple lesions that ultimately induce apoptosis. They enter the S phase of the cell cycle with unrepaired single- and double-strand breaks. Existing single-strand breaks are converted to double-strand breaks as the replication apparatus passes through. Accumulated double-strand breaks present in the S phase are repaired by homologous recombination. Homologous recombination is the preferred repair pathway as it has a much lower error rate compared to other forms of repair.

[0008] Cells that are unable to perform DNA repair by homologous recombination (e.g., due to inactivation of genes required for homologous recombination, such as breast cancer [BRCA1] or breast cancer 2 [BRCA2] mutant cells) are at risk of accumulating multiple lesions that ultimately lead to apoptosis. These cells accumulate stalled replication forks in S phase and are likely to repair DNA double-strand breaks using error-prone non-homologous end joining (NHEJ) or alternative (alt)-NHEJ pathways. Accumulation of errors in DNA by NHEJ contributes to the mutational burden that drives cancer development. Over time, the accumulation of excess DNA errors, coupled with the inability to complete S phase due to stalled replication forks, contributes to cell death (De Lorenzo et al. 2013, Jones et al. 2015). Thus, treatment with PARP inhibitors represents a new opportunity to selectively kill cancer cells. For example, tumors arising in patients with BRCA gene mutations (BRCAm) have defects in the homologous recombination DNA repair pathway and are increasingly dependent on NHEJ, alt-NHEJ and BER to maintain genomic integrity. PARP inhibitors block alt-NHEJ and BER, forcing BRCA-deficient tumors to repair double-strand breaks using error-prone NHEJ (Fong et al. 2013). Non-BRCA defects in homologous recombination DNA repair genes may also increase tumor cell sensitivity to PARP inhibitors (Gelmon et al. 2011). The basis for the anticancer activity in a subset of non-BRCAm tumors is that they share with BRCAm carriers characteristic DNA repair defects, a phenomenon broadly referred to as "BRCAness" (Turner et al. 2004). DNA repair defects can be caused by germline or somatic alterations in the homologous recombination DNA repair pathway. A recent analysis of approximately 500 high-grade serous ovarian adenocarcinomas found that approximately 50% had HRD (CGA 2011). A subset of these tumors had biologically plausible molecular alterations that may be sensitive to PARP inhibition with niraparib.Similar analyses of triple-negative breast cancers indicate that 43%–44% of these subjects have tumors with HRD (Timms et al. 2014). Homologous recombination is a complex pathway, and several genes other than BRCA1 and BRCA2 are required to sense or repair DNA double-strand breaks via the homologous recombination pathway. Thus, PARP inhibitors are selectively cytotoxic to cancer cells that are deficient in DNA repair proteins other than BRCA1 and BRCA2 (Turner et al. 2011). Recent clinical studies have shown that PARP inhibitors are effective in breast and ovarian cancer, and potentially in other cancer types (Pilie et al. 2019). Clinical anticancer activity with PARP inhibitors has been observed in subjects with and without BRCAmut; however, it is more potent in subjects with germline mutations (Kummar et al. 2012).

[0009] In summary, treatment with PARP1 / 2 inhibitors offers an opportunity to selectively kill a subset of cancer cell types by exploiting defects in DNA repair. Human cancers exhibit genomic instability and elevated mutation rates due to fundamental defects in DNA repair. Such defects render cancer cells more dependent on the remaining DNA repair pathways, and targeting these pathways is expected to have a greater impact on tumor cell survival than normal cells.

[0010] Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed for the treatment and maintenance therapy of subjects with tumors that have defects in the homologous recombination DNA repair pathway or are driven by PARP-mediated transcription factors, and is also being evaluated in subjects with HRD-negative, non-BRCA-mutated cancers.

[0011] Therefore, the administration of oregovomab, which can selectively recognize ovarian cancer, and PARP inhibitor treatment are necessary. Summary of the Invention

[0012] According to one embodiment, there is provided a method of improving the chances of survival of a patient with stage III-IV ovarian cancer, the method comprising: (a) administering to a patient with stage III-IV ovarian cancer a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) administering to said patient a therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is performed first and step (b) is performed second; Thereby increasing the chances of survival of said patients compared to control patients diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

[0013] A therapeutically effective amount of niparariv can be about 200 to about 300 mg, or 200 mg or 300 mg.

[0014] Therapeutically effective amounts of niparariv can be administered orally.

[0015] A therapeutically effective amount of monoclonal antibody mAb-B43.13 can be administered on day 1 of weeks 1, 4, 7, 12, and 20 of the treatment period.

[0016] The treatment duration can be 24 weeks.

[0017] 2 mg of mAb-B43.13 may be administered.

[0018] mAb-B43.13 can be administered by infusion over 20 minutes in a volume of 50 mL.

[0019] According to another embodiment, a therapeutic agent is provided for use in inhibiting the growth of stage III-IV ovarian cancer tumors in a patient; The therapeutic agent comprises mAb-B43.13 (oregovomab) and a PARP inhibitor; The PARP inhibitor is Niraparib; The therapeutic agent may be one of the following: (a) patients with stage III-IV ovarian cancer receiving a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) the patient is administered a therapeutically effective amount of monoclonal antibody mAb-B43.13 according to a schedule comprising administering the therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is a first step and step (b) is a second step; Thereby increasing the chances of survival of said patients compared to control patients diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

[0020] A therapeutically effective amount of niparariv can be about 200 to about 300 mg, or 200 mg, or 300 mg.

[0021] The therapeutically effective amount of niparariv can be by oral administration.

[0022] A therapeutically effective amount of monoclonal antibody mAb-B43.13 can be used on days 1, 4, 7, 12, and 20 of the treatment period.

[0023] The period of use may be 24 weeks.

[0024] 2 mg of mAb-B43.13 can be used.

[0025] mAb-B43.13 may be administered as a 20 minute infusion in a volume of 50 mL.

[0026] According to another embodiment, there is provided a use of a therapeutic agent in inhibiting the growth of a stage III-IV ovarian cancer tumor in a patient; The therapeutic agent comprises mAb-B43.13 (oregovomab) and a PARP inhibitor; The PARP inhibitor is Niraparib; The therapeutic agent may be one of the following: (a) patients with stage III-IV ovarian cancer receiving a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) the patient is administered a therapeutically effective amount of monoclonal antibody mAb-B43.13 according to a schedule comprising administering the therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is a first step and step (b) is a second step; Thereby increasing the chances of survival of said patients compared to control patients diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

[0027] A therapeutically effective amount of niparariv can be about 200 to about 300 mg, or 200 mg, or 300 mg.

[0028] The therapeutically effective amount of niparariv can be by oral administration.

[0029] A therapeutically effective amount of monoclonal antibody mAb-B43.13 can be used on days 1, 4, 7, 12, and 20 of the treatment period.

[0030] The period of use may be 24 weeks.

[0031] 2 mg of mAb-B43.13 can be used.

[0032] mAb-B43.13 may be administered as a 20 minute infusion in a volume of 50 mL.

[0033] The following terms are defined below:

[0034] The terms "administration of" and / or "administering a" are intended to mean providing an antibody, chemotherapy, and / or a combination thereof according to the present invention to a subject in need of treatment.

[0035] The term "composition" is intended to mean a product containing the specified ingredients in the specified amounts, and any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts. Such terms in relation to pharmaceutical compositions are intended to encompass products containing active and inactive ingredients that constitute a pharma-ceutically acceptable carrier, and any product resulting directly or indirectly from the combination, complexation or aggregation, or dissociation of one or more components, or other type of reaction or interaction of one or more components, of any two or more components. Thus, a pharmaceutical composition of the present invention encompasses any composition made by admixing an antibody according to the present invention with a pharma-ceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0036] The term "chemotherapeutic regimen" is intended to mean the combination of several chemotherapeutic agents. The rationale for such chemotherapy regimens is that different chemotherapy drugs act by different cytotoxic mechanisms and that the use of multiple drugs can provide a degree of synergy. Each of these has different dose-limiting adverse effects, so that the entire amount can be administered together in a chemotherapy regimen. Chemotherapy regimens include induction and maintenance regimens.

[0037] The term "induction regimen" refers to a chemotherapy regimen used for the initial treatment of a disease.

[0038] The term "maintenance regimen" is intended to mean the continued use of chemotherapy to reduce the chance that cancer will come back or to prevent existing cancer from continuing to grow.

[0039] In some embodiments, the term "pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Aqueous saline solutions, dextrose, and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. The compositions can be formulated as suppositories, using traditional binders and carriers, such as triglycerides. Oral formulations can include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions contain a therapeutically effective amount of the antibody or fragment thereof, preferably in purified form, together with a suitable amount of carrier to provide the form for proper administration to the patient. The formulation should be appropriate for the mode of administration.

[0040] As used herein in the context of the present invention, the terms "inhibit", "inhibition" or "inhibiting" mean to slow, hinder, suppress, reduce or prevent. For example, as used herein, "inhibiting the proliferation" of tumor cells means to slow, hinder, suppress, reduce or prevent the proliferation of tumor cells.

[0041] The term "administering" as used herein refers to any act that results in exposure or contact with a composition comprising a therapeutic monoclonal antibody of the present invention in combination with a disclosed chemotherapy regimen. As used herein, administration can be performed in vivo, in vitro, or ex vivo. In particular, administration is performed to an ovarian cancer patient, such as a stage III-IV ovarian cancer patient, more particularly to a stage III-IV ovarian cancer patient who is platinum sensitive and has BRCA wild type. For example, the composition can be administered by injection or endoscopy. Administration also includes applying the composition according to the present invention directly to cells. For example, during the course of surgery, tumor cells can be exposed. In accordance with one embodiment of the present invention, these exposed cells (or tumors) can be directly exposed to the composition of the present invention, for example, by washing or perfusing the surgical site and / or cells, or by directly injecting a therapeutic monoclonal antibody specific for a tumor-associated antigen in combination with at least one immunostimulatory compound and at least one immune homeostasis checkpoint inhibitor, either individually or in a mixture, into the tumor.

[0042] The term "subject" as used herein refers to a human patient or other animal, such as another mammal, that has functional mast cells, basophils, neutrophils, eosinophils, monocytes, macrophages, dendritic cells, and Langerhans cells. In humans, the appropriate cells express high affinity receptors for IgG for the administered IgG antibodies of the invention, and IgE(FcεRI) for the administered IgE antibodies of the invention. In particular, the subject can be an ovarian cancer patient, such as a stage III-IV ovarian cancer patient, more particularly a stage III-IV ovarian cancer patient that is platinum sensitive and BRCA wild type.

[0043] As used herein, the reduction or complete elimination of the growth kinetics of cancer tumor or metastatic cell or tumor is defined as meaning as understood in the art.For example, the reduction of growth kinetics means that the exponential growth, specific growth rate, or doubling time of primary solid tumor, metastatic cell, or metastatic tumor is reduced compared with the exponential growth, specific growth rate, or doubling time that is normally observed in vivo or in vitro for a given tumor type.The complete disappearance of tumor means that in the presence of a combination of a therapeutic monoclonal antibody specific for tumor-associated antigen, at least one immunostimulatory compound, and at least one immune homeostasis checkpoint inhibitor, the presence of tumor is not detected by symptoms, physical examination, or X-ray imaging, and the presence of tumor was previously confirmed by these detection methods.

[0044] The term "sufficient time for treatment" is intended to mean any period suitable for effective immunoadjuvant treatment. In embodiments, the period may be the time of a cycle used in the standard of care (e.g., chemotherapy) of the immunoadjuvant. Examples of standard of care are described, for example, in the Gynecologic Oncology Group Chemotherapy Procedures Manual, which is incorporated herein by reference. The duration of chemotherapy treatment is determined by various factors. These include the type of cancer, the extent of the cancer, the type of drug administered, as well as the expected toxicity of the drug and the time required to recover from these toxicities. Many chemotherapy treatment schedules (often referred to as standard of care (SOC), including the type and duration of chemotherapy treatment) have been determined through clinical trials to compare them and determine which are most beneficial and well tolerated. Generally, chemotherapy is administered in cycles. This allows cancer cells to be attacked when they are most vulnerable and allows the body's normal cells time to recover from the damage. There are actually three issues regarding cycle time: cycle duration, cycle frequency, and number of cycles. Cycle duration: chemotherapy can be administered as a single drug or as a combination of multiple drugs. Drugs may be administered all on one day, over several consecutive days, or continuously on an outpatient or inpatient basis. Treatment may last for minutes, hours, or days, depending on the specific protocol. Frequency of cycles: chemotherapy may be repeated weekly, biweekly, or monthly. A cycle is usually defined as one month apart. For example, two chemotherapy sessions every other week may be classified as one cycle. Number of cycles: In most cases, the number of cycles, i.e. the time from the start to the end of chemotherapy, is determined by research and clinical trials. When cure is the treatment goal. Adjuvant chemotherapy (treatment after surgery to remove all visible cancer) may last 4-6 months. Adjuvant chemotherapy is common in breast and colon cancer. In testicular cancer, Hodgkin's and non-Hodgkin's lymphoma, and leukemia, chemotherapy treatment duration may be up to one year.If there is visible disease, the duration of chemotherapy treatment will depend on the disease's response to treatment. If the disease has completely disappeared, chemotherapy may be continued for 1-2 cycles beyond this observation period to maximize the chances of attacking all microscopic disease. If the disease shrinks but does not disappear, chemotherapy is continued as long as it is tolerated and the disease does not grow. If the disease grows, chemotherapy is stopped. With increasing toxicity and blood counts in the patient, the timing of the actual cycle may be delayed according to the needs of each patient's situation. Depending on the patient's health and wishes, another drug may be given to try to kill the cancer or chemotherapy may be stopped and the goal changed to focus on the patient's comfort.

[0045] The term "PARP inhibitors" is intended to mean a class of pharmacological inhibitors of the enzyme poly ADP-ribose polymerase (PARP). PARP inhibitors approved for sale include olaparib, rucaparib, niraparib, and talazoparib. PARP inhibitors in clinical trials include, for example, talazoparib, veliparib, pamiparib, rucaparib, and veliparib.

[0046] The term "standard of care chemotherapy treatment" is intended to mean the type and duration of chemotherapy treatment that is currently accepted as the standard of care by patients with stage III-IV ovarian cancer, e.g., several cycles of paclitaxel and carboplatin treatment, without immunotherapy.

[0047] Before describing the invention in detail, certain terms are defined. As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0048] It should be noted that terms such as "preferably," "generally," and "typically" are not used herein to limit the scope of the claimed invention or to imply that a particular feature is critical, essential, or essential to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be available in a particular embodiment of the invention.

[0049] For purposes of describing and defining the present invention, it is noted that the term "substantially" is utilized herein to represent the inherent degree of uncertainty that can be attributed to any quantitative comparison, value, measurement, or other representation. The term "substantially" is also utilized herein to represent the degree to which a quantitative representation may vary from the stated reference without resulting in a change in the basic functionality of the subject matter at issue.

[0050] The features and advantages of the subject matter herein will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be understood, the subject matter disclosed and claimed can be modified in various respects without departing from the scope of the claims. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive, with the full scope of the subject matter being defined in the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The present invention is directed to a method of improving the chances of survival for patients with stage III-IV ovarian cancer using the PARP inhibitor niraparib as a first-line therapy in combination with immunotherapy. The applicant believes this is the first example of niraparib being used as a first-line therapy prior to a second-line therapy, as all compounds approved to date have been second-line therapies following chemotherapy.

[0052] In embodiments, a method of improving the chances of survival of a patient with stage III-IV ovarian cancer is disclosed, the method comprising: (a) administering to a patient with stage III-IV ovarian cancer a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) administering to said patient a therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; where step (a) is performed first and step (b) is performed second; Thereby increasing the chances of survival of said patients compared to control patients diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

[0053] The treatment duration can be 24 weeks.

[0054] Oregovomab Oregovomab (also known as mAb-B43.13) is a murine IgG1 antibody specific for CA125 (MUC16). Antibody B43.13 was deposited under the Budapest Treaty with the ATCC, 1801 University Blvd., Manassas, Va. 20110-2209, and was granted patent deposit designation PTA-1883 on May 18, 2000. [R. Madiyalakan et al, Hybridoma, 14:199-203 (1995) (incorporated herein by reference)].

[0055] A therapeutically effective amount of monoclonal antibody mAb-B43.13 can be administered on day 1 of weeks 1, 4, 7, 12, and 20 of the treatment period.

[0056] In an embodiment, 2 mg of mAb-B43.13 may be administered. According to another embodiment, 1 mg of mAb-B43.13 may be administered. According to another embodiment, mAb-B43.13 may be administered in a volume of 50 mL via a 20 minute infusion.

[0057] PARP inhibitors Poly(ADP-ribose) polymerases (PARPs), particularly PARP1 and 2, are zinc finger deoxyribonucleic acid (DNA)-binding enzymes that play an important role in DNA repair (Fong et al. 2009). When DNA breaks are formed, PARPs bind to the ends of the broken DNA strands, and this process activates their enzymatic activity.

[0058] Treatment with PARP1 / 2 inhibitors offers an opportunity to selectively kill a subset of cancer cell types by exploiting defects in DNA repair. Human cancers exhibit genomic instability and elevated mutation rates due to fundamental defects in DNA repair. Such defects render cancer cells more dependent on the remaining DNA repair pathways, and targeting these pathways is expected to have a greater impact on tumor cell survival than normal cells.

[0059] The term "PARP inhibitors" refers to a class of pharmacological inhibitors of the enzyme poly ADP-ribose polymerase (PARP). PARP inhibitors approved for sale include olaparib, rucaparib, niraparib, and talazoparib. PARP inhibitors in clinical trials include, for example, talazoparib, veliparib, pamiparib, rucaparib, and veliparib.

[0060] According to one embodiment, the PARP inhibitor is Niraparib, a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment and maintenance therapy for subjects with tumors that have defects in the homologous recombination DNA repair pathway or tumors driven by PARP-mediated transcription factors, and is also being evaluated in subjects with HRD-negative, non-BRCA-mutated cancers.

[0061] In embodiments, the therapeutically effective amount of niraparib may be about 200 to about 300 mg, or 200 mg, or 300 mg. In embodiments, the therapeutically effective amount of niraparib may be administered orally.

[0062] According to another embodiment, a therapeutic agent for use in inhibiting the growth of stage III-IV ovarian cancer tumors in a patient is disclosed, the therapeutic agent comprising mAb-B43.13 (oregovomab) and a parp inhibitor. The parp inhibitor may be niraparib. The therapeutic agent may be any of the following: (a) patients with stage III-IV ovarian cancer receiving a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) the patient may be administered a therapeutically effective amount of monoclonal antibody mAb-B43.13 according to a schedule comprising administering the therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of a treatment period; Step (a) is a first step and step (b) is a second step; Thereby increasing the chances of survival of said patients compared to control patients diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

[0063] According to one embodiment, the PARP inhibitor is Niraparib, a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment and maintenance therapy for subjects with tumors that have defects in the homologous recombination DNA repair pathway or tumors driven by PARP-mediated transcription factors, and is also being evaluated in subjects with HRD-negative, non-BRCA-mutated cancers.

[0064] In embodiments, the therapeutically effective amount of niraparib may be about 200 to about 300 mg, or 200 mg, or 300 mg. In embodiments, the therapeutically effective amount of niraparib may be administered orally.

[0065] A therapeutically effective amount of monoclonal antibody mAb-B43.13 may be administered on days 1, 4, 7, 12, and 20 of the treatment period.

[0066] In an embodiment, 2 mg of mAb-B43.13 may be administered. According to another embodiment, 1 mg of mAb-B43.13 may be administered. According to another embodiment, mAb-B43.13 may be administered in a volume of 50 mL via a 20 minute infusion.

[0067] According to another embodiment, there is disclosed the use of a therapeutic agent in inhibiting the growth of stage III-IV ovarian cancer tumors in a patient, the therapeutic agent comprising mAb-B43.13 (oregovomab) and a parp inhibitor; The PARP inhibitor is Niraparib; The therapeutic agent may be one of the following: (a) patients with stage III-IV ovarian cancer receiving a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) the patient is administered a therapeutically effective amount of monoclonal antibody mAb-B43.13 according to a schedule comprising administering the therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is a first step and step (b) is a second step; Thereby increasing the chances of survival of said patients compared to control patients diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

[0068] According to one embodiment, the PARP inhibitor is Niraparib, a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment and maintenance therapy for subjects with tumors that have defects in the homologous recombination DNA repair pathway or tumors driven by PARP-mediated transcription factors, and is also being evaluated in subjects with HRD-negative, non-BRCA-mutated cancers.

[0069] In embodiments, the therapeutically effective amount of niraparib may be about 200 to about 300 mg, or 200 mg, or 300 mg. In embodiments, the therapeutically effective amount of niraparib may be administered orally.

[0070] A therapeutically effective amount of monoclonal antibody mAb-B43.13 may be administered on day 1 of weeks 1, 4, 7, 12, and 20 of the treatment period.

[0071] In an embodiment, 2 mg of mAb-B43.13 may be administered. According to another embodiment, 1 mg of mAb-B43.13 may be administered. According to another embodiment, mAb-B43.13 may be administered in a volume of 50 mL via a 20 minute infusion.

[0072] Abbreviation [Table 1-1] [Table 1-2] [Table 1-3]

[0073] The present invention will be more readily understood by reference to the following examples, which are given to illustrate the invention, but not to limit its scope. EXAMPLES

[0074] Example 1 A Phase 1b / 2 Single-Arm Clinical Trial Evaluating the Safety and Activity of Oregovomab and Niraparib as a Combinatorial Immune Priming Strategy in Subjects with Platinum-Sensitive Recurrent Ovarian Cancer Study population: Adult subjects with CA125-related, metastatic epithelial ovarian, fallopian tube, or peritoneal cancer (FIGO stage III / IV) who have received up to three lines of prior therapy and are platinum-sensitive for ≥6 months after their most recent platinum-containing regimen prior to initiating study treatment (i.e., subjects responded to prior platinum therapy and had a progression-free interval of >6 months prior to current progression).

[0075] Number of subjects to be enrolled: Approximately 15 subjects will be screened and approximately 10 evaluable subjects will be enrolled. The Sponsor may amend the protocol to enroll up to 30 additional subjects to further evaluate the efficacy of the study after reviewing available efficacy and safety data. Protocol amendments to enroll additional subjects will be determined if 5 of 10 evaluable patients have an early humoral response at Week 7 and / or 4 of 10 evaluable patients have a disease control rate (DCR), defined as CR, PR, or SD, at the Week 12 disease assessment.

[0076] Test rationale: This is a single-arm phase 1b / 2 evaluation of oregovomab in combination with niraparib in subjects with platinum-sensitive (recurrence-free interval >6 months) ovarian, fallopian tube, and primary peritoneal cancer who have been previously treated with 1 to 3 lines of platinum-based chemotherapy.

[0077] This combination will be evaluated as a combinatorial immune priming strategy. Both drugs, oregovomab and niraparib, have been previously combined with other anticancer drugs and have shown biological activity in advanced ovarian cancer. However, they have not been combined before. PARP inhibition has proven to be compatible with immunotherapy, albeit with some bone marrow suppression (Konstantinopoulos et al. 2019). Double-stranded DNA (dsDNA fragments) resulting from treatment with niraparib should induce some immunogenic tumor cell death. dsDNA fragments have been shown to activate the innate immune STING (STimulator of INterferon Genes) sensing pathway, resulting in an enhanced IFN-γ inflammatory signature. STING activation may also reactivate immunologically inactive tumors, as shown in mouse models of other tumor types (Jing et al. 2017). In the case of combining oregovomab and niraparib in ovarian cancer, hypothetically, T cells sensitized by oregovomab may be further activated and migrate into the tumor in the presence of niraparib-mediated STING induction. One of the aims of this study is to extend the disease-free period until the next platinum-based chemotherapy, as extending the platinum-free period by immune priming with oregovomab and niraparib for 12 to 24 weeks may also improve the response to subsequent platinum-based therapy.

[0078] This study will evaluate the immunological and clinical activity, early humoral response, and DCR of combined oregovomab and oral daily niraparib. This will be a preliminary investigation of the interaction between indirect immunization with oregovomab and combination therapy with niraparib, and the immunomodulatory effects associated with PARP inhibition. The subject population, defined as ovarian cancer recurrent ≥6 months after platinum-based therapy and remaining platinum-sensitive, has received at least 1-3 lines of second-line chemotherapy and provides a reasonable and convenient window to explore the safety and antitumor activity of the combination of oregovomab and niraparib. Study subjects must be able to receive experimental immune-modifying therapy with oregovomab and niraparib under this protocol, at the discretion of the clinical investigator, where it is clinically appropriate to delay the initiation of their next line of cancer therapy for 12 weeks.

[0079] Because the clinical efficacy of the combination of oregovomab and niraparib has not yet been explored, all subjects will be treated with oregovomab and niraparib for 12 weeks, followed by evaluation of immunological and clinical activity and tumor response at week 12. An additional 12 weeks of oral niraparib will be required. For subjects with progressive disease at or before week 12, or subjects who, in the investigator's opinion, cannot tolerate niraparib due to high-grade toxicity, treatment should be switched to an alternative next-line cancer therapy. Regardless of the treatment chosen after the initial 12 weeks of oregovomab and niraparib, all subjects will be treated with one additional dose of single-agent oregovomab at week 20. Clinical response will be reassessed at week 24.

[0080] We also review the long-standing interplay between oregovomab-induced immune stimulation and PARP-mediated antitumor effects, as well as its recently recognized ability to boost the immune system, which may enhance responses to subsequent cancer treatment. Progression-free survival (PFS) status from long-term follow-up may provide further preliminary information supporting immune priming in this combination treatment strategy.

[0081] The doses tested for each component in this study were previously selected through human clinical trials. Establishing safety and observing activity of co-exposure will justify further evaluation in frontline and other recurrent disease settings.

[0082] In summary, this study evaluates the immunological, clinical activity, and tolerability of the combination therapy in the setting of platinum-sensitive recurrent ovarian cancer.

[0083] Rationale for the 2 mg oregovomab dose: The dose of oregovomab is optimal for use in the immunization protocol. Because oregovomab is administered at an immune stimulating dose rather than a pharmacological dose, the combination is expected to be well tolerated, but this will be explored in controlled clinical trials. The dose of oregovomab is in the optimal range to induce cellular immunity and decreases with higher antibody doses. Oregovomab immunizations are performed five times over 20 weeks, with 2 mg administered intravenously over 20 minutes ± 5 minutes at weeks 1, 4, 7, 12, and 20.

[0084] Rationale for the 300 mg Niraparib Dose: The 300 mg dose of niraparib is the optimal pharmacological dose clinically approved for use in ovarian cancer, balancing enzyme inhibition against toxicity. This dose of niraparib has toxicities not seen with oregovomab, notably myelosuppression (neutropenia, thrombocytopenia, anemia) in 20-40% of subjects and hypertension / hypertensive crisis in 9% of subjects treated for up to 2 years. Despite some myelosuppression, PARP inhibition has been demonstrated to be compatible with immunotherapy, as reported in the initial report at ASCO 2017 (Friedlander, 2017) and seen in unpublished studies.

[0085] Recently, management of bone marrow toxicity has been simplified by reducing the oral dose from 300 mg to 200 mg daily based on baseline body weight or platelet count, reducing the adverse effect on platelet counts while maintaining clinical activity.

[0086] This dose reduction was based on the ENGOT-OV16 / NOVA and PN001 studies and a model classification tree approach that showed that subjects with baseline weight <77 kg or baseline platelet counts <150,000 μL had an approximately 30% incidence of grade 3 / 4 thrombocytopenia during the first 30 days of treatment. Furthermore, the actual delivered dose in these subjects approximated the 200 mg starting dose, despite the intended 300 mg starting dose.

[0087] In the study, subjects will be treated with a starting dose of 300 mg niraparib (three tablets of 100 mg each). Subjects with baseline weight <77 kg or baseline platelet count <150,000 μL will be treated with a starting dose of 200 mg niraparib (two tablets of 100 mg each of niraparib).

[0088] Study design:

[0089] A phase 1b / 2 single-arm, open-label study evaluating the combination of oregovomab and niraparib as an immune-priming strategy in subjects with platinum-sensitive recurrent ovarian cancer.

[0090] The exams include:

[0091] Screening Period (up to 28 days): After signing informed consent, subjects are screened for eligibility during the 28 days immediately prior to starting study medication at the Week 1 Day 1 visit. After meeting all eligibility criteria, subjects are enrolled and treatment begins.

[0092] Treatment duration (approximately 24 weeks): All subjects will receive a combination of niraparib and oregovomab as follows: Niraparib will be administered orally once daily beginning on day 1 of treatment (day 1 of week 1). The daily dose of niraparib will be 300 mg (3 x 100 mg tablets) administered orally from day 1 of week 1 through at least the end of week 12. For subjects with baseline weight <77 kg or baseline platelet count <150,000 μL, the daily dose of niraparib will be 200 mg (2 x 100 mg tablets). Olegovomab (2 mg) will be administered as an intravenous infusion over 20 ± 5 minutes in 50 mL saline at visits on Day 1 of Weeks 1, 4, 7, 12, and 20.

[0093] Subjects will be observed for 1-2 hours after completion of the oregovomab infusion.

[0094] All clinical, safety, and immunological evaluations will be performed according to a defined schedule throughout the treatment and survival follow-up periods (see Appendix A).

[0095] The treatment period is defined as the period from the start of the first study treatment to the end of the treatment period, which is defined as week 24 or early termination.

[0096] Subjects with progressive or unknown disease [PD / UNK] per RECIST v1.1 or who are intolerant to niraparib due to high-grade toxicity as assessed by the investigator at week 12 will discontinue niraparib and begin an alternative next-line chemotherapy of the investigator's choice.

[0097] Participants who achieve stable disease [SD], partial response [PR] or complete response [CR] by RECIST v1.1 at week 12 will continue receiving niraparib.

[0098] All participants are required to receive the fifth dose of oregovomab at week 20, regardless of whether they continue receiving niraparib.

[0099] Post-treatment follow-up period: The initial safety follow-up was 30 days after the last dose of the last treatment given.

[0100] Long-term follow-up: PFS and safety data, including information on interval treatment, will be collected every 3 months [± 1 week] until death, withdrawal of consent, loss to follow-up, or the sponsor's decision to terminate the study, whichever occurs first, for up to 1 year from the end of the treatment period. If subjects are unable to visit in person, these follow-up visits may be conducted by telephone.

[0101] Diagnosis and main inclusion / exclusion criteria:

[0102] Main entry criteria: Subjects are eligible to participate in this study only if they meet all of the following criteria:

[0103] 1. Adult women (18 years or older)

[0104] 2. Patients with CA125-associated recurrent epithelial adenocarcinoma of ovarian, fallopian tube or peritoneal origin.

[0105] 3. Eligible histological epithelial cell type: Serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed cell carcinoma, transitional cell carcinoma, malignant Brenner tumor, or adenocarcinoma not otherwise specified (NOS).

[0106] 4. Previously treated FIGO stage III and IV disease with at least one platinum-based therapy and up to three lines, each line modified for recurrence, progression or toxicity. Bevacizumab, hormonal therapy and / or PARP inhibitor maintenance therapy are not considered lines of treatment.

[0107] 5.Having received 1-3 lines of chemotherapy including platinum-based chemotherapy for initial ovarian cancer, but being platinum-sensitive, defined as ovarian cancer that recurred ≥6 months after platinum-based therapy prior to study treatment initiation.

[0108] 6. Have a medical assessment that predicts survival for at least 6 months and it is clinically appropriate to withhold cytotoxic therapy for 12 weeks based on the treating investigator's best clinical judgment.

[0109] 7. Serum CA125 elevated to >50 units / mL as measured at screening within 28 days of starting study treatment.

[0110] 8. Have measurable disease, including identification of marker lesions by radiographic or physical criteria suitable for evaluation per RECIST v1.1, for documentation of response or disease progression.

[0111] 9.ECOG performance status is 0, 1 or 2.

[0112] 10. Organ function is adequate as defined as: Absolute neutrophil count ≥ 1,500 / μL b. Platelets ≧100,000 / μL C. Hemoglobin ≥ 8 g / dL Total bilirubin ≤ 1.5 x ULN (≤ 2.0 in subjects with known Gilbert syndrome) or direct bilirubin ≤ 1 x ULN e.LDH, SGOT, SGPT < 2.5 times the upper limit of normal f. Albumin > 3.5 g / dL g. Serum creatinine ≦ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance by Cockcroft-Gault formula ≧ 30 mL / min

[0113] 11. Females of childbearing potential must have a negative pregnancy test and be willing to avoid pregnancy using highly effective contraception from the first dose of study treatment until 60 days after the last dose of study treatment.

[0114] 12. Ability to take oral medication.

[0115] 13. Sign an informed consent and authorization authorizing the disclosure of personal health information.

[0116] Key exclusion criteria: Subjects will be excluded from the study if they meet any of the following criteria:

[0117] 1. Subjects must not be receiving concurrent treatment in other interventional clinical trials.

[0118] 2. Subjects must not have undergone major surgery ≤3 weeks prior to initiating protocol treatment and must have recovered from the effects of surgery.

[0119] 3. Subjects must not have received treatment with an investigational drug for ≤ 4 weeks or for a period of at least 5 half-lives of the investigational drug (whichever is shorter) prior to starting protocol treatment.

[0120] 4. Subject has received radiation therapy involving >20% of bone marrow within 2 weeks or has received radiation therapy within 1 week prior to protocol treatment day 1.

[0121] 5. Subject must not have received a blood transfusion (platelets or red blood cells) within ≤ 2 weeks prior to the first dose of study treatment.

[0122] 6. Subjects must not have received colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior to initiating protocol treatment.

[0123] 7. Subject has experienced known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to previous chemotherapy, lasting >4 weeks and related to most recent treatment.

[0124] 8. Subjects must not have any serious uncontrolled medical illness, non-malignant systemic disease, active uncontrolled infection, or active infection causing fever. Examples include, but are not limited to, uncontrolled grand mal seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or psychiatric illness that would prohibit obtaining informed consent. Subjects with well-controlled chronic illnesses (e.g., diabetes, hypertension [<150sBP and <90dBP]) are eligible.

[0125] 9. Evidence of clinically significant cardiovascular or respiratory disease, such as myocardial infarction within 1 year, uncontrolled or unstable angina, congestive heart failure (New York Heart Association class III or IV), arrhythmia (grade 2 or greater), chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 5 years.

[0126] 10. Subject must not have a history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

[0127] 11. Has been diagnosed with or treated for another malignancy within 5 years prior to first dose, or has previously been diagnosed with another malignancy with evidence of residual disease. Subjects with non-melanoma skin cancer or cervical cancer in situ are not excluded if they have undergone complete resection.

[0128] 12. Subject must not have known symptomatic brain or leptomeningeal metastases.

[0129] 13. If you have an active autoimmune disease (e.g., rheumatoid arthritis, SLE, ulcerative colitis, Crohn's disease, MS, ankylosing spondylitis, thyroiditis) that requires ongoing immunosuppressive therapy.

[0130] 14. Subjects with immune deficiencies such as cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; subjects with inherited or congenital immune deficiencies (HIV infection, see below).

[0131] 15. Receiving chronic treatment with systemic immunosuppressants such as cyclosporine, methotrexate, adrenocorticotropic hormone (ACTH), or immunosuppressant monoclonal antibodies.

[0132] 16. Use of chronic therapeutic corticosteroids, defined as taking prednisone or equivalent for >5 days, except for patients on inhalers or in preplanned steroid taper. (Note: Premedication with corticosteroids per institutional standard of care is permitted.)

[0133] 17.Has had a history of treatment with oregovomab.

[0134] 18. Known allergy to mouse proteins or hypersensitivity to any of the excipients in oregovomab or niraparib.

[0135] 19. Use of pressor agents (e.g., SC epinephrine), especially monoamine oxidase inhibitors (MAOIs), is contraindicated.

[0136] 20. Any of the following conditions (testing during the study is not required): a. Known HIV infection, unless on effective antiretroviral therapy and have had an undetectable viral load within the last 6 months; or b. For active infection, known or suspected hepatitis B (subjects with chronic hepatitis B infection must have undetectable HBV viral load with suppressive therapy, if necessary; positivity for surface antibodies alone is not an exclusionary condition), or c. Known or suspected hepatitis C infection that has not been cured through treatment (unless the patient has an undetectable viral load while undergoing treatment).

[0137] You are unable to understand or are unwilling to sign the release forms that must be obtained before treatment.

[0138] [Table 2-1] [Table 2-2]

[0139] Test period: Subjects will receive treatment for approximately 24 weeks during the treatment phase, enter a post-treatment follow-up phase after an initial 30-day safety follow-up, and then be followed for survival until death, withdrawal of consent, loss to follow-up, decision by the sponsor to terminate the study up to one year after the end of treatment, or earlier termination. Recruitment and treatment will be completed within approximately 12 months, and the entire study, including the follow-up period, is expected to last approximately two years.

[0140] Study treatment:

[0141] Investigational Product (IP): Oregovomab (MAb-B43.13) Dosage form: freeze-dried formulation Dosage: 2 mg, administered over 20 ± 5 minutes Administration method / location: Intravenous / in clinic Frequency: In clinic on days 1 of weeks 1, 4, 7, 12, and 20 (see timing and event schedule).

[0142] Concomitant medication: Niraparib Form: Tablets ·Dose: 300mg (100mg x 3 tablets) · Method / place of administration: Oral / at home Frequency: Daily for all subjects until the end of Week 12, then daily from Weeks 12 through 24 at the investigator's discretion.

[0143] Comparator medication: Not applicable.

[0144] Placebo: Not applicable.

[0145] Pre-existing and concomitant medications:

[0146] Medications or killed vaccines (including over-the-counter or prescription medications, vitamins, and / or herbal supplements) administered at the time of subject enrollment or during the study that are deemed to be for the supportive care and safety of the subject must be recorded in the eCRF with the reason for use, dates of administration including start and end dates, and administration information including dose and frequency.

[0147] For oregovomab, the use of pre- and post-infusion medications to prevent or treat infusion reactions is permitted. Subjects may be pretreated with corticosteroids (e.g., dexamethasone), diphenhydramine, and H2 antagonists (e.g., cimetidine or ranitidine).

[0148] Subjects must inform the investigator of any new medications taken after starting study medication. All medications (other than study medication) and significant non-pharmacological therapies (including physical therapy, herbal / natural medicines, and blood transfusions) administered during the study must be documented in the eCRF.

[0149] Concomitant medications other than those listed above may be considered on a case-by-case basis by the investigator in consultation with the medical monitor, if necessary.

[0150] Concomitant medications or medications to be taken with caution:

[0151] For oregovomab: Monoamine oxidase inhibitors (MAOIs) should be avoided if possible due to their potential interactions with antihypertensives (e.g., SC epinephrine) that may cause severe hypertension. Systemic administration of immunosuppressants (e.g., corticosteroids, methotrexate, or immunosuppressant monoclonal antibodies) with which subjects are chronically treated is prohibited. Subjects previously treated with chronic immunosuppressants must have discontinued treatment for at least 8 weeks prior to study initiation.

[0152] Other investigational drugs within 30 days of Week 1, Day 1, or during the study.

[0153] Prohibited or cautionary treatments for niraparib:

[0154] Systemic anti-cancer or biologic therapy.

[0155] ·Immunotherapy.

[0156] [Table 3]

[0157] ·Chemotherapy.

[0158] Investigational drugs other than niraparib and oregovomab

[0159] Radiation therapy involving >20% of bone marrow is prohibited within 2 weeks prior to and during study treatment Day 1. Note: Small-field palliative radiation therapy may be permitted >1 week prior to study treatment Day 1.

[0160] Surgery involving tumor involvement. Note: The administration of radiation therapy or surgery involving tumor involvement is considered progressive disease at the time of the procedure.

[0161] Niraparib is a weak inducer of cytochrome P450 (CYP) 1A2 in vitro and a relatively poor substrate of P-glycoprotein (P-gp); investigators are encouraged to use caution with CYP1A2 substrates with narrow therapeutic ranges, i.e., theophylline and tizanidine.

[0162] Prophylactic cytokines (i.e., granulocyte-colony stimulating factor [GCSF]) should not be administered in the first cycle of the study but may be administered in subsequent cycles in accordance with current American Society of Clinical Oncology (ASCO) guidelines.

[0163] Biomarker Analysis:

[0164] Pharmacokinetic Analysis: Individual subject PK parameters will not be collected in this study.

[0165] Statistical methods: Sample size determination: The sample size of 10 subjects is estimated to be sufficient to allow an initial descriptive assessment of safety interactions of the combination therapy and to provide preliminary evidence of clinical and immune response patterns.

[0166] Analysis population: The intent to treat (ITT) analysis population will include all subjects who received the first treatment in the study. The ITT analysis population will be the primary analysis population for all efficacy endpoints and demographics.

[0167] The per-protocol (PP) population will include all evaluable subjects who have received at least three doses of oregovomab and have no significant protocol violations that could impact efficacy evaluations. The PP population will be used as a supportive population for efficacy endpoints.

[0168] The safety population will include all subjects who received any dose of study drug (niraparib or oregovomab) and will be the primary analysis population for safety endpoints.

[0169] Secondary endpoint analysis: Progression-free survival will be calculated from the date of first study treatment to the earliest date of disease progression or death as determined by the local radiologist / investigator. Overall survival will be calculated from the date of first study drug administration to the date of death.

[0170] Safety: Safety will be assessed by treatment-emergent adverse events (TEAEs) per CTCAE v5.0, physical examination, laboratory tests, and vital signs.

[0171] Analysis time points Data analysis will be performed at the following times:

[0172] Interim analysis after at least 10 evaluable subjects completed 12 weeks of treatment.

[0173] The primary analysis will be performed after all subjects have completed 24 weeks of total treatment and 30 days of safety follow-up.

[0174] To be included in the interim analysis, the following criteria had to be met:

[0175] Participants must have received at least three doses of oregovomab.

[0176] Subjects must have biologic response (e.g., CA125 / HAMA) data available (screening and at least one post-treatment sample).

[0177] Subjects have completed at least two imaging evaluations.

[0178] At least 10 evaluable patients will be enrolled and three arms will be analyzed:

[0179] 1. All patients enrolled in the study (intention-to-treat analysis). DCR, HAMA, and LTFU will be considered.

[0180] 2. Patients received niraparib for the entire 24-week study period.

[0181] 3. Patients who switched to alternative therapy after week 12, with week 12 as the baseline

[0182] A Clinical Study Report (CSR) will be generated after the last subject completes 30-day safety follow-up. The sponsor reserves the option to generate a CSR addendum to take into account long-term survival data, if available.

[0183] Data Safety Monitoring Committee: This trial will not have a formal Data Safety Monitoring Board (DSMB).

[0184] Instead, a Safety and Data Review Committee (SDRC), consisting of investigators and representatives from the sponsor, will be established to monitor safety during the trial.

[0185] Independent Review Committee: This trial does not have an Independent Review Committee (IRC).

[0186] steering committee: There will be no steering committee for this exam.

[0187] Background Introduction Ovarian cancer accounts for 5% of all cancer deaths in women, the fifth most common among all cancers, and the fourth most common among the 40-57 age subgroup. It is estimated that there will be approximately 22,530 new cases and 13,980 deaths from ovarian cancer in the United States in 2019 (ACS 2019). A woman's lifetime risk of developing ovarian cancer is approximately 1.3% at birth, and the risk of dying from ovarian cancer is almost 1.0%, with little distinction by race. This corresponds to an annual mortality rate of 9.5 deaths per 100,000 women. Ovarian cancer can be considered a dangerous cancer, with symptoms being subtle and nonspecific, and approximately 80% of cases being diagnosed when local or distant metastases have already occurred. Approximately 70% of cases are diagnosed at ages over 54 years (median: 63 years), and the median age of death from recurrent ovarian cancer is 70 years. The 5-year survival rate for ovarian cancer is approximately 47% (ACS 2019).

[0188] Complete responses after initial treatment with surgery and chemotherapy (platinum and taxane regimens) are common (>50%), but one-half of tumors recur within two years after cytoreductive surgery for stage III and stage IV disease, often without curative treatment. Mortality has decreased by approximately 2.2% per year over the past decade, but there is still considerable room for improvement in treatment to minimize recurrence rates, extend the time to recurrence, and improve overall survival. Once recurrent, there is often no curative treatment, and recurrent ovarian cancer is usually fatal.

[0189] Existing (or available) treatments and their effectiveness The NCCN Guidelines version 1.2019 suggests that no single therapeutic agent should currently be recommended as a treatment of choice for recurrent ovarian cancer. Several regimens and agents are recommended based on expert opinion, primarily due to reduced toxicity and / or slightly increased efficacy.

[0190] For platinum-sensitive recurrences, platinum-based combination chemotherapy is recommended. Single-agent carboplatin or cisplatin is preferred for subjects with platinum-sensitive disease who cannot tolerate combination therapy. Preferred combinations for platinum-sensitive disease include carboplatin / paclitaxel, carboplatin / liposomal doxorubicin, and carboplatin / gemcitabine with or without bevacizumab. Although prolonging the platinum-free interval has been associated with improved outcomes, strategies to artificially extend this interval with nonplatinum regimens do not appear to improve survival outcomes compared with platinum-based regimens.

[0191] Maintenance therapy is increasingly being used in the treatment of ovarian cancer. Subjects with platinum-sensitive recurrent disease may be treated with a combination of carboplatin and paclitaxel or gemcitabine with bevacizumab, or bevacizumab alone may be administered as maintenance therapy. OCEANS, a phase 3 trial evaluating subjects with platinum-sensitive disease treated with gemcitabine and carboplatin with and without bevacizumab, also showed improved PFS, but no difference in OS (Aghajanian et al. 2012). GOG-0213 showed that the addition of bevacizumab to standard chemotherapy followed by maintenance therapy until progression improved median overall survival in subjects with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, a sensitivity analysis based on adjusted treatment-free interval stratification suggested that this strategy may be an important addition to the use of bevacizumab (Coleman et al. 2017). The AURELIA trial evaluated treatment of subjects with platinum-resistant disease with single-agent chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) alone or in combination with bevacizumab and improved PFS but not OS (Pujade-Lauraine et al. 2014).

[0192] Alternative agents of choice for maintenance therapy are poly ADP-ribose polymerase (PARP) inhibitors, several of which have been approved and are being increasingly used for this treatment. The PARP inhibitors niraparib, olaparib, and rucaparib are approved by the FDA for subjects with platinum-sensitive recurrent ovarian cancer who have had a partial or complete response to platinum-based chemotherapy (see prescribing information).

[0193] Niraparib is approved for the maintenance treatment of adult subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a complete or partial response to platinum-based chemotherapy. Niraparib is also approved for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have received three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either harmful or suspected harmful BRCA mutations or genomic instability and has progressed more than six months after a response to the last platinum-based chemotherapy.

[0194] · Olaparib is approved for the maintenance treatment of adult subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a complete or partial response to platinum-based chemotherapy, and for the treatment of adult subjects with adverse or suspected adverse germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have received 3 or more lines of prior chemotherapy, based on an FDA-approved companion diagnostic for olaparib. An additional indication is the treatment of adult subjects with adverse or suspected adverse BRCAm advanced ovarian cancer who have received 3 or more lines of chemotherapy, selected for treatment based on an FDA-approved companion diagnostic for olaparib.

[0195] Rucaparib is approved for the maintenance treatment of adult subjects with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a complete or partial response to platinum-based chemotherapy, and for the treatment of adult subjects with deleterious BRCA mutation-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more lines of chemotherapy, based on an FDA-approved companion diagnostic for rucaparib.

[0196] Description of study drug Oregovomab Oregovomab is an investigational monoclonal antibody in clinical trials as an immunotherapy treatment (indirect immunization) for ovarian cancers expressing the tumor-associated antigen CA125 (MUC16). CA125 is a surface glycoprotein antigen expressed on most non-mucinous epithelial ovarian cancers. Because it is shed into the blood, elevated serum concentrations can be used as a marker of ovarian cancer activity (Fendrick et al, 1993). CA125 is associated with a 200-250 kDa high molecular weight mucin-like glycoprotein complex with a complex structure (Fendrick et al, 1993; Yin et al, 2002) and may also be expressed in other inflammatory conditions of the peritoneal mucosa, making this marker nonspecific to be used effectively as a cancer screen for the general population. CA125 is most often elevated above the normal range in the presence of ovarian cancer, making it a useful marker of disease activity when subjects with ovarian cancer are followed longitudinally.

[0197] The active ingredient of oregovomab (formerly Ovarex®) is the murine monoclonal antibody B43.13, an immunoglobulin of the IgG1κ subclass that binds CA125 with high affinity (1.16 × 10 10 Its interaction with circulating and tissue-associated CA125 modulates the immune response to tumor antigens and is the basis for its therapeutic activity.

[0198] Oregovomab has a unique mechanism of action (MOA) based on immunological stimulation following binding to CA125. Current evidence supports that this binding in vivo renders the target antigen CA125 more immunogenic, or "neo-antigen-like," by altering and enhancing antigen processing and presentation to specific T cells. This induces antigen-antibody uptake and processing using immunoglobulin Fcγ binding, a binding pattern unique to mouse IgG1 in humans, resulting in cross-presentation of CA125 peptides and initiation of local specific immune responses with an IFN-γ signature. These properties mount demonstrable humoral and cellular responses in CA125-positive cancer subjects, who are otherwise in a state of relative immune tolerance to the disease. Oregovomab has been shown to have enhanced activity, particularly when combined with selected chemotherapy in specific schedules, in the frontline treatment of stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following optimal cytoreductive surgery with residual disease less than 1 cm.

[0199] This application of monoclonal antibody technology differs from classical active immunization, which induces protective immunity (requiring administration of intact molecules, molecular fragments, or genetic sequences of antigens and their expression in situ), or passive immunization, which directly targets the disease using mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), which requires the administration of large amounts of specific antibodies. Indirect immunization involves repeated transient exposure to low doses of specific antibodies, avoiding overall antibody excess and allowing immune-stimulatory antigen processing in the tumor microenvironment and additional systemic sites. The induction of cellular immunity targeting tumor antigens is thought to be the main mechanism of action. This principle has been explored with multiple antigen systems, notably targeting CA125 in ovarian cancer.

[0200] Indirect immunization with oregovomab is an approach to increase immune recognition of CA125 in cancer subjects and initiate antitumor immune responses. Previous studies have shown that such immune initiation alone is insufficient to alter the clinical course of the disease in immunosuppressive malignancies (Berek et al. 2004, Berek et al. 2009), but further attention to the immunomodulatory properties of scheduled concomitant cancer treatments may impact subject outcomes.

[0201] In 2009, Braly published a randomized phase 2 trial in subjects with post-surgery frontline stage III or stage IV disease. Here, one group of subjects received oregovomab (2 mg per infusion) simultaneously with the standard chemotherapy carboplatin and paclitaxel, while the other received it 1 week after chemotherapy. The trial showed that the group receiving the concurrent immunochemotherapy had a better immune response, using several orthogonal indices (contrary to what was traditionally thought, given the immunosuppressive effects of chemotherapy) (Braly et al. 2009). Schedule dependence was detected with assays of humoral responses to the administered antibodies and with a prototype assay of cellular immunity to CA125 using an enzyme-linked immunosorbent spot (ELISPOT) assay platform. Early humoral responses measured after 6 weeks were detected in 75% of patients who received the chemoimmunotherapy preferred schedule, compared with 35% of patients who received the alternative chemoimmunotherapy delayed schedule (Braly et al. 2009). These data supported further clinical investigation in the randomized phase 2 trial QPT-ORE-002. The final results, published as Brewer et al. 2020 and Battaglia et al. (translated results) (CII 2020.) and described below, show that the addition of oregovomab to a standard chemotherapy regimen of paclitaxel / carboplatin after optimal cytoreductive surgery results in clinically significant improvements in PFS and OS with little additional toxicity in subjects with stage III and IV epithelial ovarian, fallopian tube, or primary peritoneal cancer.

[0202] These QPT-ORE-002 Phase 2 results support the concept that schedule-dependent addition of oregovomab to chemotherapy regimens such as paclitaxel / carboplatin significantly improves efficacy via a unique MOA with minimal additional toxicity (very favorable safety profile), and reinforce the improved efficacy paradigm of supplementing oregovomab with non-chemotherapeutic agents such as niraparib, known to be effective as maintenance therapy in adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have partially responded to platinum-based chemotherapy.

[0203] Niraparib Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed for the treatment and maintenance therapy of subjects with tumors that have defects in the homologous recombination DNA repair pathway or are driven by PARP-mediated transcription factors, and is also being evaluated in HRD-negative, non-BRCA-mutated subjects.

[0204] Poly(ADP-ribose) polymerases (PARPs), PARP1 and 2, are Zn-finger deoxyribonucleic acid (DNA)-binding enzymes that play an important role in DNA repair (Fong et al. 2009). When DNA breaks are formed, PARPs bind to the ends of the broken DNA strands, and this process activates their enzymatic activity.

[0205] Activated PARP catalyzes the addition of long polymers of adenosine diphosphate (ADP)-ribose to PARP and several other proteins associated with chromatin, including histones and various DNA repair proteins (De Lorenzo et al. 2013, Jones et al. 2015). As a result, chromatin relaxes and DNA repair proteins are rapidly recruited, resulting in efficient repair of DNA breaks. Thus, PARP plays a key role in sensing DNA damage and transducing it into intracellular signals that activate base excision repair (BER) and single-strand break repair pathways.

[0206] Normal cells repair up to 10,000 DNA lesions every day, with single-strand breaks being the most common form of DNA damage. Cells unable to repair such a load of DNA damage, such as those with defects in homologous recombination or the BER pathway, are at risk of accumulating multiple lesions that ultimately induce apoptosis. They enter the S phase of the cell cycle with unrepaired single- and double-strand breaks. Existing single-strand breaks are converted to double-strand breaks as the replication apparatus passes through. Accumulated double-strand breaks present in the S phase are repaired by homologous recombination. Homologous recombination is the preferred repair pathway as it has a very low error rate compared to other forms of repair.

[0207] Cells unable to repair DNA by homologous recombination (e.g., due to inactivation of genes required for homologous recombination, such as breast cancer [BRCA1] or breast cancer 2 [BRCA2] mutant cells) are at risk of accumulating multiple lesions that ultimately lead to apoptosis. These cells have stalled replication forks in S phase and are likely to repair DNA double-strand breaks using error-prone non-homologous end joining (NHEJ) or alternative (alt)-NHEJ pathways. Accumulation of DNA errors by NHEJ contributes to the mutational burden that drives cancer development. Over time, the accumulation of excessive DNA errors, coupled with the inability to complete S phase due to stalled replication forks, contributes to cell death (De Lorenzo et al. 2013, Jones et al. 2015). Thus, treatment with PARP inhibitors may represent a new opportunity to selectively kill cancer cells. For example, tumors arising in patients with germline BRCA mutations (gBRCAmut) have defects in the homologous recombination DNA repair pathway and are increasingly dependent on NHEJ, alt-NHEJ and BER to maintain genomic integrity. PARP inhibitors block alt-NHEJ and BER, forcing tumors with BRCA deficiencies to repair double-strand breaks using error-prone NHEJ (Fong et al. 2013). Non-BRCA defects in homologous recombination DNA repair genes may also enhance tumor cell sensitivity to PARP inhibitors (Gelmon et al. 2011). The basis for the anticancer activity in a subset of non-BRCAmut tumors is that they share with BRCAmut carriers characteristic DNA repair defects, a phenomenon broadly referred to as "BRCAness" (Turner et al. 2004). DNA repair defects can be caused by germline or somatic alterations in the homologous recombination DNA repair pathway. A recent analysis of approximately 500 high-grade serous ovarian adenocarcinomas found that approximately 50% had HRD (CGA 2011). A subset of these tumors had biologically plausible molecular alterations that may be sensitive to PARP inhibition with niraparib.Similar analyses of triple-negative breast cancers indicate that 43%–44% of these subjects have tumors with HRD (Timms et al. 2014). Homologous recombination is a complex pathway, and several genes other than BRCA1 and BRCA2 are required to sense or repair DNA double-strand breaks via the homologous recombination pathway. Thus, PARP inhibitors are selectively cytotoxic to cancer cells that are deficient in DNA repair proteins other than BRCA1 and BRCA2 (Turner et al. 2011). Recent clinical trials have shown that PARP inhibitors are effective in breast and ovarian cancer, and potentially in other cancer types (Pilie et al. 2019). Clinical anticancer activity with PARP inhibitors has been observed in subjects with and without BRCAm; however, it is more potent in subjects with germline mutations (Kummar et al. 2012).

[0208] In summary, treatment with PARP1 / 2 inhibitors offers a novel opportunity to selectively kill a subset of cancer cell types by exploiting defects in DNA repair. Human cancers exhibit genomic instability and elevated mutation rates due to fundamental defects in DNA repair. Such defects render cancer cells more dependent on remaining DNA repair pathways, and targeting these pathways is expected to have a greater impact on tumor cell survival than normal cells. The rationale for combining niraparib with oregovomab is detailed below.

[0209] Preclinical experience with oregovomab Nonclinical Pharmacology Oregovomab MAb-B43.13 selectively binds to adenocarcinomas expressing the CA125 antigen, while showing no significant cross-reactivity with selected human normal organs and tissues. MAb-B43.13 does not exhibit antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) properties either in vitro or in vivo. MAb-B43.13 induces strong humoral responses in normal rats, normal rabbits, and tumor-bearing mice. Cellular responses were prominent in tumor-bearing mice. Biological activity was demonstrated in tumor-bearing mice, revealing both increased survival and reduced tumor size after treatment with Oregovomab MAb-B43.13 compared to controls.

[0210] For more detailed information, see oregovomab MAb-B43.13IB.

[0211] Pharmacokinetics in animals In both normal and tumor-bearing mice, the distribution of 99mTc-labeled MAb B43.13 showed no abnormal accumulation in normal organs and tissues, with gradual loss of the tracer over time. In tumor-bearing animals, the compound was shown to accumulate preferentially in tumor xenografts expressing CA-125 compared with an isotype-matched control antibody.

[0212] For more detailed information, see oregovomab MAb-B43.13IB.

[0213] toxicology Acute toxicity tests in male and female rats and female rabbits showed no significant acute toxicity in either species, even at 100 times the estimated human dose (2 mg / 60 kg body weight). Subacute toxicity tests in female rabbits showed similar results at 100 times the human dose.

[0214] For more detailed information, see oregovomab MAb-B43.13IB.

[0215] Preclinical experience with niraparib Nonclinical Pharmacology Preclinical data on niraparib are detailed in Niraparib IB. Briefly, in preclinical models, niraparib has been observed to inhibit normal DNA repair mechanisms and induce synthetic lethality when administered to cells with HRD. In xenograft studies of BRCA1 mutants, oral administration of niraparib resulted in tumor regression, with tumor weight reduced by >90% compared to controls. In xenograft studies of BRCA2 mutants, mice treated with niraparib showed 55%-60% growth inhibition of both tumor burden and tumor weight.

[0216] Niraparib demonstrated robust antitumor activity in vivo in BRCA1-mutated breast cancer (MDA-MB-436), BRCA2-mutated pancreatic cancer (CAPAN-1), and patient-derived Ewing sarcoma mouse models.Using patient-derived ovarian and breast cancer xenograft models, niraparib demonstrated activity in both BRCAmut and BRCA wild-type tumors.

[0217] Clinical Experience Because this is a first-in-human study of the combination of oregovomab and niraparib, no data exist on the combination, and we provide information from experience with each drug separately.

[0218] clinical safety Oregovomab A total of 963 ovarian cancer subjects were investigated in 10 clinical trials conducted between 1997 and 2008 (649 subjects treated with oregovomab and 314 subjects treated with placebo). In addition, an additional 97 patients with ovarian cancer (94 subjects in the safety population: 46 subjects treated with oregovomab + paclitaxel / carboplatin and 48 subjects treated with placebo + paclitaxel / carboplatin) were investigated in QPT-ORE-002 conducted between 2011 and 2018. In summary, oregovomab or placebo was administered at a dose of 2 mg / 50 mL as a 20-minute intravenous infusion to a total of 1,057 subjects with ovarian cancer. The number of doses per subject ranged from 1 to 20.

[0219] For clinical safety details, please see oregovomab MAb-B43.13IB.

[0220] Niraparib The primary data supporting the safety of treatment with niraparib came from the NOVA trial, in which a total of 546 subjects received the study treatment.

[0221] All 367 subjects receiving niraparib and 171 of 179 subjects receiving placebo (96%) experienced at least one treatment-emergent adverse event (TEAE). The higher rate of TEAEs in the placebo group reflects the burden of prior chemotherapy and the subjects' underlying ovarian cancer. When data were examined across study cohorts for TEAE incidence, results were generally similar in the gBRCAmut and non-gBRCAmut cohorts. In the overall safety population, niraparib had a higher incidence of grade 3 or 4 TEAEs (74% vs. 23%), serious adverse events (SAEs) (30% vs. 15%), TEAEs leading to treatment interruption (67% vs. 15%), TEAEs leading to dose reduction (69% vs. 5%), and TEAEs leading to treatment discontinuation (15% vs. 2%) in the niraparib vs. placebo arms. No treatment-emergent deaths were reported.

[0222] The most common non-hematologic TEAEs (all grades) in the niraparib-treated group compared with placebo-treated subjects were nausea (74% vs. 35%), fatigue (46% vs. 32%), constipation (40% vs. 20%), and vomiting (34% vs. 16%). The majority of non-hematologic TEAEs were mild to moderate in severity. The most common hematologic TEAEs (all grades) observed with niraparib were anemia (49%), thrombocytopenia (46%), thrombocytopenia (20%), and neutropenia (18%). Grade 3 or 4 hematologic AEs were common at study treatment initiation, but no serious clinical sequelae were observed, and relatively few subjects discontinued study treatment due to these AEs. Dose adjustments based on individual tolerability during the first three cycles significantly reduced the incidence of these AEs beyond the third cycle, demonstrating the overall effectiveness of the dose adjustment approach. These TEAEs can be routinely monitored using standard assessment of hematological laboratory values, similar to routine monitoring for ovarian cancer subjects undergoing anticancer drug therapy.In the NOVA study, niraparib dose adjustments tended to occur early, with most subjects reaching their individual adjusted dose levels by the end of the 3rd month of treatment (i.e., the 3rd cycle).

[0223] Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have been observed in subjects treated with the PARP inhibitor olaparib. Due to their shared mechanism of action, MDS and AML are potential risks for subjects treated with niraparib. In the phase 3 NOVA study, the incidence of MDS / AML in subjects receiving niraparib (5 of 367; 1.4%) was similar to that in subjects receiving placebo (2 of 179; 1.1%). Guidance is provided on monitoring subjects for new AEs of MDS / AML and follow-up of subjects with suspected MDS / AML.

[0224] The PR-30-5011-C1 study (NOVA corrected QT interval [QTc] substudy, n=26) was an open-label study evaluating the effect of niraparib on QTc measurements in subjects with histologically diagnosed ovarian, fallopian tube, or primary peritoneal cancer. No clinically significant electrocardiogram (ECG) changes, including QTc interval prolongation, were reported attributable to niraparib. Niraparib administered at therapeutic doses did not prolong the QT interval. No correlation was observed between niraparib exposure (i.e., plasma concentration) and change in QTc (i.e., change in corrected QT interval calculated using the Fridericia formula [ΔQTcF]).

[0225] For details on clinical safety, please see Niraparib IB.

[0226] Niraparib Baseline Platelet Count and Body Weight as Predictors of Thrombocytopenia An analysis was performed using data collected in ENGOT-OV16 / NOVA and the first Phase I study, PN001. The analysis found that baseline platelets influenced platelet nadir. Low baseline platelet counts (<180 × 10 9 TEAEs occurred in most subjects regardless of weight, but grade ≥3 TEAEs, SAEs, and TEAEs leading to dose modification or treatment discontinuation occurred more frequently in the cohort weighing <58 kg than in the cohort weighing ≥77 kg. In the cohort weighing <58 kg, approximately 80% of subjects underwent dose reduction compared with 59% in the cohort weighing ≥77 kg. Treatment discontinuation was more prevalent in subjects with lower weight (24%) compared with subjects in the highest weight quartile (10%).

[0227] The potential relationship between body weight and TEAEs was further explored in an analysis to evaluate the correlation between grade 3 or 4 thrombocytopenia and baseline body weight. The lowest platelet counts during the first 30 days were plotted against baseline body weight to see whether lower body weight identified subgroups of subjects with higher levels of thrombocytopenia during cycle 1. During the first 30 days of treatment, a baseline body weight of ≥77 kg was associated with a lower incidence of grade 3 or 4 thrombocytopenia (14%) compared with a body weight of <58 kg (43%).

[0228] Finally, a classification tree approach was used to refine the optimal cutoff point for predicting the likelihood of a subject developing ≥ grade 3 thrombocytopenia within 30 days after the first dose of niraparib (Berek et.al, 2018). The model results show that in the subgroup of subjects with baseline body weight < 77 kg or baseline platelet count < 150,000 μL, the incidence of grade 3 / 4 thrombocytopenia during the first 30 days was 35.4%, compared with 11.5% in the group of subjects with body weight > 77 kg and platelet count > 150,000 μL. Furthermore, the average daily dose was 258 mg throughout the first two cycles in subjects with body weight > 77 kg and platelet count > 150,000 μL, compared with only 206 mg in subjects with body weight < 77 kg or platelet count < 150,000 μL. Thus, despite the intended delivery of a starting dose of 300 mg, the actual dose delivered approximated the starting dose of 200 mg. Additionally, a retrospective analysis of NOVA showed that dose reductions did not compromise efficacy, as previously shown in the phase 3 PRIMA / ENGOT-OV26 / GOGG-3012 study evaluating maintenance niraparib versus placebo after response to platinum-based chemotherapy in subjects with newly diagnosed, high-grade, advanced serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer (unpublished data). These findings will be confirmed in the current study, which enrolls study treatment at 200 mg (2 tablets of niraparib) in subjects with baseline weight <77 kg and baseline platelet counts <150,000 μL.

[0229] Clinical Efficacy Oregovomab The final results of QPT-ORE-002 mentioned above, which are relevant to the concept that oregovomab has enhanced activity when added to other anticancer drugs, are as follows: A phase 2 prospective randomized trial (QPT-ORE-002) recruited 97 subjects at 13 centers in the United States and Italy. Subjects received paclitaxel-carboplatin-olegovomab or paclitaxel-carboplatin alone. A total of 97 subjects with previously untreated advanced epithelial ovarian, adnexal or primary peritoneal cancer, stage III and stage IV, were treated after optimal cytoreductive surgery (residual disease <1 cm in diameter) at 10 centers (Italy and United States) and followed up for 3 years after treatment.

[0230] The final results showed that subjects treated with oregovomab + paclitaxel / carboplatin had a clinically significant improvement in PFS (median 41.8 months) compared to paclitaxel / carboplatin alone (median 12.2 months) by KM method (p=0.0027), with a HR of 0.44 by multivariate Cox PH method (p=0.0029). Subjects treated with oregovomab + paclitaxel / carboplatin had a clinically significant improvement in OS (median NE) compared with paclitaxel / carboplatin alone (median 43.2 months) by KM (p=0.0042), with a HR of 0.34 by multivariate Cox PH (p=0.0077), and a clinically significant improvement in time to clinical progression (TTCP) (median 43.1 months) compared with paclitaxel / carboplatin (median 13.6 months) by KM (p=0.0014), with a HR of 0.40 by multivariate Cox PH (p=0.0019).

[0231] For details on clinical efficacy, please refer to oregovomab MAb-B43.13IB.

[0232] A Phase 3 Study of Niraparib Monotherapy in Platinum-Sensitive Recurrent Ovarian Cancer Recently, results have been published showing that niraparib is more effective than placebo as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (NOVA trial) and that niraparib is effective as monotherapy in the fourth or later line of treatment (QUADRA trial), both of which are relevant background for the proposed oregovomab + niraparib trial.

[0233] NOVA Exam The randomized, double-blind, phase 3 NOVA trial (Niraparib Maintenance Therapy in Platinum-Sensitive Recurrent Ovarian Cancer) randomized a total of 553 subjects across 107 centers worldwide (Mirza, 2016). The aim of the study was to evaluate the efficacy of niraparib versus placebo as maintenance therapy in subjects with platinum-sensitive recurrent ovarian cancer. Subjects were stratified according to the presence or absence of gBRCAmut in their tumors (gBRCA vs non-gBRCA cohorts) and the type of non-gBRCAmut, and randomized in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily (QD). The primary endpoint was PFS. The study enrolled 203 subjects in the gBRCAmut cohort and 350 subjects in the non-gBRCAmut cohort. Of the 350 non-gBRCAmut cohort, 162 had tumors identified as HRD positive (HRDpos) and 134 were HRD negative (HRDneg). HRD status was not determined for 54 subjects.

[0234] Demographic and baseline characteristics were well balanced. Table 1 below shows the results of the primary PFS endpoint in each of the three primary efficacy populations (i.e., gBRCAmut, HRDpos, and non-gBRCAmut cohorts). Additionally, the median PFS in subjects with HRDneg tumors was 6.9 months (95% confidence interval [CI]: 5.6, 9.6) in the niraparib arm vs. 3.8 months (95% CI: 3.7, 5.6) in the placebo arm, with a HR of 0.58 (95% CI: 0.361, 0.922) (p=0.0226).

[0235] [Table 4]

[0236] QUADRA Study Clinical activity of PARP inhibitors (PARPi) as monotherapy has also been reported in the setting of recurrent ovarian cancer treatment in the QUADRA (Moore et al, 2019) trial (NCT02354586). The aim of this latest study was to explore later-stage treatment options for ovarian cancer subjects with few effective options, where the proportion of subjects achieving an overall response is typically less than 10%, and where median overall survival after third-line treatment is 5-9 months. This study investigated the efficacy of niraparib monotherapy beyond fourth-line treatment.

[0237] Four hundred and sixty-three subjects with HRD-positive tumors (with or without BRCA mutations) sensitive to the last platinum-based therapy and who had received three or four prior chemotherapy regimens were treated with single-agent niraparib. Subjects with prior exposure to PARP inhibitors were excluded. Subjects without BRCA mutations had to have been at least 6 months after their last dose of platinum-based therapy. HRD status was determined using Myriad myChoice CDx as tumor BRCA mutation (tBRCAm) (n=63) and / or genomic instability score (GIS) ≥42 (n=35). All subjects received niraparib 300 mg once daily until disease progression or unacceptable toxicity.

[0238] The primary efficacy outcomes were objective response rate (ORR) and duration of response (DOR), assessed by investigator using RECIST v1.1. Among 98 subjects in the HRD-positive cohort, the ORR was 24% (95% CI: 16, 34); all were partial responses. The estimated median DOR was 8.3 months (95% CI: 6.5, not estimable). In subjects with tBRCAm ovarian cancer, the ORR was 39% (7 / 18; 95% CI: 17, 64) in subjects with platinum-sensitive disease, 29% (6 / 21; 95% CI: 11, 52) in subjects with platinum-resistant disease, and 19% (3 / 16; 95% CI: 4, 46) in subjects with platinum-refractory disease. Thirteen of 47 subjects (28%) in the primary efficacy population achieved an overall response (95% CI: 15.6-42.6; one-sided p=0.00053). This represents clinically meaningful activity of niraparib in heavily pretreated women with ovarian cancer, particularly those with HRD-positive platinum-sensitive disease, including those with BRCA mutations as well as those with BRCA wild-type disease. No new safety signals were identified.

[0239] For details on clinical efficacy, please see Niraparib IB.

[0240] Clinical Pharmacokinetics Oregovomab Based on data from the OVA-Gy-01 study, the apparent terminal half-life (t 1 / 2z The mean residence time (MRT) is approximately 45 hours, with a plasma clearance of approximately 110 mL / min. Just under 50% of the radiotracer dose is excreted in the urine, presumably as free 99m It is excreted in the form of technetium. Repeated administration enhances clearance due to the generation of an early humoral response against this heterologous immunogenic antibody.

[0241] For more information, see oregovomab MAb-B43.13IB.

[0242] Niraparib For details, please see Niraparib IB.

[0243] Rationale for the test This study is a single-arm, open-label, phase 1b / 2 evaluation of the combination of oregovomab (an indirect immunomonoclonal antibody specific for the ovarian cancer antigen CA125) and niraparib (an orally administered poly ADP-ribose polymerase enzyme inhibitor) as a combinatorial immune priming strategy in subjects with platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer.

[0244] Both drugs, oregovomab and niraparib, have been previously combined with other anticancer drugs and have shown biological activity in advanced ovarian cancer. However, the two drugs have not been used together before. Although there is some myelosuppression, PARP inhibition has proven to be compatible with immunotherapy (Konstantinopoulos et al. 2019). The dsDNA fragments generated by treatment with niraparib should induce some immunogenic tumor cell death. dsDNA fragments have been shown to activate the innate immune STING (STimulator of INterferon Genes) sensing pathway and enhance the IFN-γ inflammatory signature. STING activation may also reactivate immunologically inactive tumors, as shown in mouse models of other tumor types (Jing et al. 2017). The data showed that pancreatic cancer progression was potently inhibited by STING agonists, reactivating immunologically inactive pancreatic tumors and promoting the trafficking and activation of tumor-killing T cells. In the case of the combination of oregovomab and niraparib in ovarian cancer, hypothetically, T cells immunized by oregovomab could be further activated and trafficked into the tumor in the presence of niraparib-mediated STING induction.

[0245] The study will primarily evaluate the immunological and clinical activity of the combination of oregovomab and niraparib. It will also preliminarily explore the impact on safety of combining the indirect immunity of oregovomab with the immune stimulatory activity of PARP inhibition. The subject population with platinum-sensitive recurrent disease (defined as ovarian cancer recurrent at least 6 months after platinum-based therapy and at second- or fourth-line therapy) provides a reasonable and convenient time frame after the most recent recurrence to explore the potential interactions and antitumor activity of the combination of oregovomab and niraparib. At the investigator's discretion, it must be determined clinically appropriate to delay the initiation of next-line therapy for 12 weeks while study subjects receive experimental immune-modulating therapy with oregovomab and niraparib under this protocol.

[0246] Because clinical response to the combination of oregovomab and niraparib has not yet been investigated, all subjects will be treated with oregovomab and niraparib therapy for 12 weeks to assess initial humoral activity and DCR at week 12. If DCR (defined here as SD, PR, or CR) is confirmed in 4 of 10 patients, they will receive an additional 12 weeks of oral niraparib unless the investigator determines that the subject should be switched to an alternative next-line cancer treatment. If progression is observed at or before week 12, subjects should discontinue niraparib and be immediately switched to an alternative cancer treatment. After the initial 12 weeks of oregovomab and niraparib, all subjects, regardless of treatment choice, will receive one additional dose of oregovomab alone at week 20. Clinical response will be reassessed at week 24.

[0247] In addition to the potential for response, the long-term consequences of the interplay between the immune stimulation and PARP-mediated antitumor effects of oregovomab, and its recently recognized ability to boost the immune system, may also enhance responses to subsequent cancer treatments. Data from long-term follow-up (progression-free and overall survival status) may provide additional preliminary information supporting promising combination sequences to further explore not only the improved survival in response to the oregovomab + niraparib combination, but also its potential impact in altering the immune environment leading to subsequent more effective treatments.

[0248] The doses tested for each component in this study were previously selected through human clinical trials. Establishing the DCR in this study and observing early humoral activity of this combination will justify further evaluation in frontline and other recurrent disease settings.

[0249] In summary, this study will primarily evaluate the potential of the drug combination alone to induce humoral activity and DCR and / or enhance response to subsequent treatment and survival, and will confirm the safety of the combination.

[0250] Benefit / Risk Assessment The potential for enhancing the efficacy of oregovomab in combination with niraparib while minimizing increased toxicity needs to be established. This combination, with the schedule-dependent addition of oregovomab to niraparib, may significantly improve efficacy on clinically significant endpoints (ORR, survival) with a unique MOA, along with a favorable safety profile, and may represent an advance over available therapies in the management of platinum-sensitive ovarian cancer. Furthermore, the interplay between the immune stimulatory effects of oregovomab and its antitumor effects via PARP may improve efficacy against subsequent cancer treatments.

[0251] Oregovomab Dose Justification A fixed dose of 2 mg of oregovomab administered by slow infusion over 20 minutes (±5 minutes) is suitable for indirect immunization with low doses of antibodies and for immune induction against self-antigens. This dose of oregovomab is in the optimal range for inducing cellular immunity, which is diminished with higher doses of antibodies. Early imaging studies of radiolabeled oregovomab (Mab-43.13) at a dose level of 2 mg were intended to optimize signal-to-noise and limit anti-mouse antibody interactions during repeated injections. This dose was maintained in many subsequent therapeutic clinical trials because of the observed improvements in clinical outcomes and immunological responses. Furthermore, multiple studies administering oregovomab 2 mg on various schedules support the current dose (Braly et al. 2009; Brewer et al. 2020).

[0252] Niraparib Dosing Justification The 300mg dose of niraparib is the optimal pharmacological dose clinically approved for use in ovarian cancer, balancing enzyme inhibition against toxicity. At this dose, niraparib has toxicities not seen with oregovomab, most notably myelosuppression (neutropenia, thrombocytopenia, anemia) in 20-40% of subjects and hypertension / hypertensive crisis in 9% of subjects treated for up to 2 years. Although PARP inhibition is myelosuppressive, it has been demonstrated to be compatible with immunotherapy, as reported in the initial ASCO 2017 report (Friedlander, 2017) and acknowledged in unpublished studies (Tesaro, internal data).

[0253] Recently, management of myelotoxicity has been simplified by reducing the oral dose from 300 mg to 200 mg per day based on either baseline body weight and / or platelet count, reducing the adverse effect on platelet counts while maintaining clinical activity.

[0254] This dose reduction is based on the ENGOT-OV16 / NOVA and PN001 studies and a model classification tree approach that showed that subjects with baseline weight <77 kg and / or baseline platelet count <150,000 μL had approximately 30% lower incidence of grade 3 / 4 thrombocytopenia during the first 30 days of treatment. Furthermore, the actual delivered dose in these subjects approximated the starting dose of 200 mg, even though a starting dose of 300 mg was intended. In this study, subjects will be treated with niraparib 300 mg (3 tablets of niraparib). Subjects with baseline weight <77 kg or baseline platelet count <150,000 μL will receive a daily dose of niraparib of 200 mg (2 tablets of niraparib 100 mg).

[0255] Objectives and Evaluation Items

[0256] [Table 5]

[0257] Study design Overall design A phase 1b / 2 single-arm, open-label study evaluating the combination of oregovomab and niraparib as an immune priming strategy in subjects with platinum-sensitive recurrent ovarian disease.

[0258] Approximately 15 subjects will be screened and approximately 10 evaluable subjects will be enrolled. The Sponsor may amend the protocol to enroll up to 30 additional subjects to further evaluate the efficacy of the study after reviewing available efficacy and safety data. The decision to amend the protocol to enroll additional subjects will be based on the observation of an early humoral response at week 7 in 5 of 10 evaluable patients and / or a disease control rate (DCR), defined as CR, PR, or SD, of 40% at the disease assessment at week 12 in 4 of 10 evaluable patients. The study includes:

[0259] Screening period (up to 28 days before the start of study treatment) After signing informed consent, subjects are screened for eligibility during the 28 days immediately prior to starting study medication at the Week 1 Day 1 visit. If all eligibility criteria are met, subjects are enrolled and treatment begins.

[0260] Treatment duration (approximately 24 weeks): All eligibility criteria are reviewed and once met, subjects will be offered study treatment.

[0261] All subjects will receive the combination of niraparib and oregovomab as follows:

[0262] Niraparib (300 mg) orally administered once daily starting on day 1 of treatment (week 1, day 1). The daily dose of niraparib will be (100 mg x 3 tablets) orally administered from week 1, day 1 through the end of week 12. Subjects with baseline weight <77 kg or baseline platelet count <150,000 μL will receive a daily niraparib dose of 200 mg (2 x 100 mg niraparib tablets).

[0263] Medications should be taken at home at approximately the same time each day. Bedtime dosing is a possible method of managing nausea.

[0264] o Each tablet must be swallowed whole.

[0265] 〇It can be taken with or without food.

[0266] If a dose is missed, subjects must take their next dose at their regularly scheduled time.

[0267] If a subject vomits or misses a dose, no additional dose should be administered.

[0268] *Subjects must bring their pill bottle with them to each visit to ensure study drug accountability by clinic staff.

[0269] Olegovomab (2 mg) will be administered as an intravenous infusion over 20 ± 5 minutes in 50 mL saline at visits on Day 1 of Weeks 1, 4, 7, 12, and 20.

[0270] On the clinic day, subjects will receive niraparib followed 1-2 hours later by oregovomab, unless niraparib is taken at bedtime. Subjects will be observed for 1-2 hours after the oregovomab infusion has completed.

[0271] All clinical, safety, and immunological evaluations will be performed according to a defined schedule during the treatment and survival follow-up periods (see Appendix A). The treatment period is defined as the period from the start of the first study treatment to the end of the treatment period, which is defined as week 24 or early termination.

[0272] Subjects with progressive or unknown disease [PD / UNK] by RECIST v1.1 at week 12 may discontinue niraparib and switch to an alternative treatment of the physician's choice.

[0273] Participants who achieve stable disease [SD], partial response [PR] or complete response [CR] by RECIST v1.1 at week 12 may continue receiving niraparib or be switched to an alternative treatment of the physician's choice.

[0274] All participants are required to receive the fifth dose of oregovomab at week 20, regardless of whether they continue receiving niraparib.

[0275] Imaging studies for disease assessment will be performed using RECIST v1.1 at baseline, week 12, and week 24 visits. Subsequent imaging will be performed according to institutional guidelines. Subjects will be treated until end of treatment at week 24, discontinuation due to disease progression, loss to follow-up, withdrawal of consent, treatment with another anticancer agent, or death.

[0276] During treatment, subjects will continue to complete all clinical, safety, and immunological evaluations according to the established schedule (see Appendix A).

[0277] End of treatment: The treatment period is defined as the period from the start of the first study treatment to the end of treatment, which is defined as week 24 or early termination. Subjects will enter the post-treatment follow-up period, as described below, unless study treatment is discontinued before the end of the treatment period. If a subject terminates the treatment period before receiving all scheduled doses of study treatment for the following reasons:

[0278] Progression of disease: Participants will enter a post-treatment follow-up period where they will be monitored for safety and then survival (see below).

[0279] For reasons other than disease progression: Subjects will enter a post-treatment follow-up period and will continue to be followed for safety and disease activity assessments according to RECIST v1.1, Appendix A (see "Post-treatment Follow-up Period" below for details).

[0280] Investigator's decision, consent withdrawal, loss to follow-up or death: No further information will be collected from the subject, but the Sponsor will retain and continue to use data collected prior to the withdrawal of consent or date of last contact.

[0281] Post-treatment follow-up period · Safety Follow-up: All subjects will be followed for safety for at least 30 days after the end of treatment.

[0282] Long-term follow-up: All subjects will be followed up for survival approximately every 3 months [± 2 weeks] for one year until death, withdrawal of consent, loss to follow-up, or the sponsor's decision to terminate the study, whichever occurs first.

[0283] Information collected during LTFU will include all subsequent chemotherapy treatments (including start / end dates, reasons for regimen changes, and best response to each regimen). Date / cause of death will also be collected.

[0284] Duration of treatment Subjects will receive treatment for approximately 24 weeks during the treatment period, enter post-treatment follow-up with 30 days of safety follow-up, and then be followed for survival for up to one year until death, withdrawal of consent, loss to follow-up, or the sponsor's decision to terminate the study. Recruitment of the first 10 subjects is expected to be completed within approximately six months, and the overall duration of the study, including the one-year follow-up period, is expected to last approximately two years. The study may be proportionately longer depending on whether additional subjects are enrolled if there are safety or efficacy issues that require a larger data pool.

[0285] Research End End of study (EOS) for a particular subject will be defined as the time point when the subject completes follow-up assessments or discontinues as detailed in the respective time and event schedule.

[0286] The end of the overall study will be defined as one year after the date of the last follow-up visit of the last subject in the follow-up period or if the sponsor decides to end the study earlier.

[0287] Study population Pre-approved protocol deviations from recruitment and enrollment criteria, also known as protocol waivers or exceptions, will not be permitted.

[0288] Inclusion criteria Subjects are eligible for inclusion in the study only if they meet all of the following criteria:

[0289] 1. Adult women (18 years or older)

[0290] 2. Subject with CA125-associated recurrent epithelial adenocarcinoma of ovarian, fallopian tube or peritoneal origin.

[0291] 3. Eligible histological epithelial cell type: Serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed cell carcinoma, transitional cell carcinoma, malignant Brenner tumor, carcinosarcoma, or adenocarcinoma not otherwise specified (NOS).

[0292] 4. Previously treated FIGO stage III and IV disease with up to 3 lines of prior therapy including at least one platinum-based therapy. Each line of therapy must be modified for recurrence, progression or toxicity. Bevacizumab, hormonal therapy and / or PARP inhibitor maintenance therapy are not considered lines of treatment.

[0293] 5.Has received platinum-based chemotherapy for first-line ovarian cancer, but must have been platinum-sensitive for ≥6 years following the most recent platinum-containing regimen prior to starting study treatment.

[0294] 6. Medically assessed prognosis for at least 6 months survival and, based on the investigator's best clinical judgment, a 12-week interruption of cytotoxic therapy is clinically appropriate.

[0295] 7. Serum CA125 elevated to >50 units / mL as measured at screening within 28 days of starting study treatment.

[0296] 8. Have measurable disease, including identification of marker lesions, by radiographic or physical criteria suitable for evaluation per RECIST v1.1 for documentation of disease response or progression.

[0297] 9.ECOG performance status of 0 or 1.

[0298] 10. Adequate organ function as defined below: Absolute neutrophil count ≥ 1,500 / μL b. Platelets ≧100,000 / μL C. Hemoglobin ≥ 9 g / dL Total bilirubin ≤ 1.5 x ULN (≤ 2.0 in subjects with known Gilbert syndrome) or direct bilirubin ≤ 1 x ULN e.LDH, SGOT, SGPT < 2.5x upper limit of normal f. Albumin > 3.5 g / dL g. Serum creatinine ≦ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance by Cockcroft-Gault formula ≧ 30 mL / min

[0299] 11. Females of childbearing potential must have a negative pregnancy test and be willing to avoid pregnancy using highly effective contraception from the first dose of study treatment until 60 days after the last dose of study treatment.

[0300] 12. Ability to take oral medication.

[0301] 13. Sign an informed consent and authorization authorizing the disclosure of personal health information.

[0302] Exclusion criteria Subjects will be excluded from the study if they meet any of the following criteria:

[0303] 1. Subjects must not be undergoing concurrent interventional clinical trials.

[0304] 2. Subjects must not have undergone major surgery ≤ 3 weeks prior to beginning protocol treatment and must have recovered from the effects of surgery.

[0305] 3. Subject must not have received any investigational treatment within ≤ 4 weeks or at least 5 half-lives of the investigational drug, whichever is shorter, prior to starting protocol treatment.

[0306] 4. Subject has received radiation therapy involving >20% of bone marrow within 2 weeks; or has received radiation therapy within 1 week prior to protocol treatment day 1.

[0307] 5. Have not received a blood transfusion (platelets or red blood cells) within ≤2 weeks prior to the first dose of study treatment.

[0308] 6. Subjects must not have received colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior to initiating protocol treatment.

[0309] 7. Subject had confirmed grade 3 or 4 anemia, neutropenia, or thrombocytopenia from prior chemotherapy that persisted for >4 weeks and was related to the most recent treatment.

[0310] 8. Subjects must not have any serious uncontrolled medical illness, non-malignant systemic disease, or active uncontrolled infection or fever-causing active infection, such as, but not limited to, uncontrolled grand mal seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric illness that would prohibit obtaining informed consent. Subjects with well-controlled chronic illnesses (e.g., diabetes, hypertension [<150sBP and <90dBP]) are eligible.

[0311] 9. Evidence of clinically significant cardiovascular or respiratory disease, including myocardial infarction within 1 year, uncontrolled or unstable angina, congestive heart failure (New York Heart Association class III or IV), arrhythmia (grade 2 or greater), chronic obstructive pulmonary disease, persistent asthma, or history of asthma within 5 years.

[0312] 10. Subject must not have a history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

[0313] 11. Has been diagnosed with or treated for another malignancy within 5 years prior to first dose, or has previously been diagnosed with another malignancy with evidence of residual disease. Subjects with non-melanoma skin cancer or cervical intraepithelial neoplasia are not excluded if they have undergone complete resection.

[0314] 12. Subject must not have known, symptomatic brain or leptomeningeal metastases.

[0315] 13. If you have an active autoimmune disease (e.g., rheumatoid arthritis, SLE, ulcerative colitis, Crohn's disease, MS, ankylosing spondylitis, thyroiditis) that requires ongoing immunosuppressive therapy.

[0316] 14. Subjects with immune deficiencies such as cellular immunodeficiency, hypogammaglobulinemia or dysgammaglobulinemia; subjects with inherited or congenital immune deficiencies (HIV infection, see below).

[0317] 15. Receiving chronic treatment with systemic immunosuppressants such as cyclosporine, methotrexate, adrenocorticotropic hormone (ACTH), or immunosuppressant monoclonal antibodies.

[0318] 16. Use of chronic therapeutic corticosteroids, defined as taking prednisone or equivalent for >5 days, except for patients on inhalers or preplanned steroid tapers. (Note: Premedication with corticosteroids per institutional standard of care is permitted.)

[0319] 17.Has had a history of treatment with oregovomab.

[0320] 18. Known allergy to mouse proteins or hypersensitivity to any of the excipients in oregovomab or niraparib.

[0321] 19. There is a contraindication to the use of pressor agents (e.g., SC epinephrine), especially monoamine oxidase inhibitors (MAOIs).

[0322] 20. Any of the following conditions (testing during the study is not required): a. Known HIV infection, unless on effective antiretroviral therapy and have had an undetectable viral load within the last 6 months; or b. For active infection, known or suspected hepatitis B (subjects with chronic hepatitis B infection must have undetectable HBV viral load with suppressive therapy, if necessary; positivity for surface antibodies alone is not an exclusionary condition), or c. Known or suspected hepatitis C infection that has not been cured through treatment (unless the patient has an undetectable viral load while undergoing treatment).

[0323] 21. Unable to understand and / or unwilling to sign the release form that must be obtained prior to treatment.

[0324] Screening failures Subjects who sign informed consent but fail to start treatment for any reason will be considered screen failures. The reason why treatment was not started will be collected. The minimum information collected for screen failures will include demographics, reason for screen failure, and any serious adverse events (SAEs) that occurred during the screening period.

[0325] Subject replacement / rescanning Subjects who have received at least one dose of any study drug will not be replaced. Subjects who are screened but have not received any study drug may be replaced.

[0326] Potentially eligible subjects who fail screening on any single criterion may be rescreened once using the same screening number.

[0327] Treatment of subjects A study intervention is defined as any investigational intervention, commercial product, or medical device intended to be administered to a study subject according to a study protocol.

[0328] The "study drugs" are the experimental biologic agent oregovomab and the PARP inhibitor niraparib.

[0329] "Investigational Treatment Drug" refers to the investigational drug(s) administered alone or in combination and at the timing and frequency outlined in the Schedule of Events (Appendix A).

[0330] Details of the study medications are shown in Table 3.

[0331] Study Drug Information

[0332] [Table 6]

[0333] Treatment Allocation This study will not be randomized or stratified.

[0334] Study drug administration All subjects will receive a combination of niraparib and oregovomab. For details, please refer to the pharmacy manual.

[0335] On the day of the visit, subjects will first receive niraparib, followed 1-2 hours later by oregovomab. Subjects will be observed for 1-2 hours after the end of the oregovomab infusion, during which time they will be monitored for possible allergic symptoms, including anaphylaxis, such as fever, chills, dizziness, nausea, headache, diarrhea, dyspnea, tachypnea, hypotension, and tachycardia. Subjects who receive multiple doses of oregovomab or have been exposed to the mouse protein may experience severe or life-threatening allergic reactions.

[0336] If such a reaction occurs, a physician must be prepared to treat the subject immediately; epinephrine, antihistamines, and corticosteroids must be available.

[0337] If niraparib is delayed, oregovomab should be similarly delayed and administered in the same sequence as above.

[0338] Niraparib Niraparib will be administered continuously in a flat, fixed container once daily according to Table 3 below. Niraparib tablets should be swallowed whole and should not be opened, crushed, or chewed. Food does not significantly affect the absorption of niraparib; niraparib can be taken without food. Subjects should take the dose at approximately the same time each day. Bedtime dosing is a potential method of managing nausea.

[0339] Do not make up for vomit.

[0340] If a subject misses a dose of niraparib (more than 12 hours after the usual dosing time), they should skip that dose and take the next dose at the scheduled time.

[0341] If niraparib is reduced, subjects should be instructed to continue using the new dose until their current supply is depleted.

[0342] Subjects must be instructed to return any unused study medication to the site upon discontinuation or completion of treatment. Site personnel must ensure that appropriate doses of each study medication are administered and that investigational drug accountability is performed and documented.

[0343] [Table 7]

[0344] Weeks 1 to 12: The daily dose of niraparib will be (3 x 100 mg tablets) administered orally from Day 1 of Week 1 through the end of Week 12. Subjects with baseline weight <77 kg or baseline platelet count <150,000 μL will receive a daily dose of 200 mg (2 x 100 mg niraparib tablets).

[0345] Subjects must bring their medication bottle and completed pill diary to each visit to ensure accountability of study medication to clinic staff.

[0346] Week 13 to 24 Participants who achieve stable disease [SD], partial response [PR], or complete response [CR] by RECIST v1.1 at week 12 may continue receiving niraparib for an additional 12 weeks (24 weeks total) or switch to an alternative anti-cancer regimen of the investigator's choice.

[0347] Oregovomab At visits on Day 1 of Weeks 1, 4, 7, 12, and 20, a dose of 2 mg in 50 mL of saline will be administered as an intravenous infusion over 20 minutes ± 5 minutes.

[0348] All subjects were required to receive a fifth dose of oregovomab at week 20, regardless of whether treatment was administered beyond week 12.

[0349] Dose Modifications Niraparib After the first cycle, non-hematologic or hematologic toxicity may lead to dose interruptions and / or modifications of niraparib at the investigator's discretion.

[0350] Treatment must be interrupted for any Common Terminology Criteria for Non-Hematologic Adverse Events (CTCAE) grade 3 or 4 AEs determined by the investigator to be related to niraparib administration (Table 5). If non-hematologic toxicities have adequately resolved to baseline or grade ≤1 within 4 weeks (28 days) of the dose interruption period, subjects may resume treatment with niraparib, with dose reduction if prophylaxis is deemed not feasible (see Table 4). If an event of similar or higher grade recurs, treatment must be interrupted again and, upon resolution, further dose reductions must be made according to Table 4.

[0351] Subjects must permanently discontinue treatment with niraparib if toxicity requiring dose interruption does not resolve completely within the maximum 4-week (28-day) dose interruption period or does not become CTCAE Grade 1, and / or the subject has already been tapered to a minimum dose of 100 mg QD.

[0352] Niraparib dose interruption and modification criteria for hematological parameters are based on blood counts and are outlined in Table 6. If hematological toxicity has not resolved to the specified levels within 4 weeks (28 days) of the interruption period, subjects must permanently discontinue treatment with niraparib.

[0353] For subjects initially receiving 3 tablets per day (300 mg / day), a reduction to 2 tablets per day (200 mg / day) and then to 1 tablet per day (100 mg / day) will be permitted. No further reductions will be permitted.

[0354] For subjects initially receiving 2 tablets (200 mg / day), a reduction to 1 tablet (100 mg / day) once daily will be permitted. No further reductions will be permitted.

[0355] [Table 8]

[0356] [Table 9]

[0357] [Table 10-1] [Table 10-2]

[0358] In the case of thrombocytopenia, after its initial occurrence, treatment may be resumed at the same dose or at the next lower dose level once hematologic toxicity has resolved. If it occurs subsequently, the dose must be reduced when treatment is resumed. If the platelet count does not recover to ≥ 100,000 / μL within 28 days after interruption, the study treatment should be discontinued.

[0359] If dose interruptions and / or changes are required at any time during study treatment due to hematologic toxicity, weekly blood draws for complete blood counts (CBCs) will be monitored until AEs have resolved to the designated blood count levels. To ensure safety of the new dose, weekly CBCs will be required for an additional 4 weeks after resolution of AEs, after which 4-weekly monitoring will resume. CBC monitoring will continue every 4 weeks (i.e. monthly) for the next 11 months of treatment and periodically thereafter.

[0360] Subjects requiring platelet or red blood cell transfusions (≥ 1 unit) must undergo dose reduction upon recovery if study treatment is restarted.

[0361] If MDS / AML is diagnosed by a hematologist, subjects must permanently discontinue study treatment.

[0362] For surgical procedures during study treatment, interruption of study medication for up to 4 weeks (28 days) will be permitted.

[0363] Oregovomab No dose modifications or reductions will be permitted for oregovomab. If necessary for a suspected infusion reaction, at the investigator's discretion, the oregovomab infusion may be interrupted for up to 2 hours before resuming, and the infusion time may be extended to 40-60 minutes with standard antihistamines, corticosteroids, and / or epinephrine medications used as needed in accordance with institutional guidelines for infusion reactions.

[0364] Infusion reactions leading to discontinuation of oregovomab must be fully resolved within 2 hours or resolve to CTCAE Grade 1.

[0365] In consultation with the medical monitor, subjects may be rechallenged with caution, with or without premedication with corticosteroids and / or antihistamines.

[0366] If an AE of CTCAE grade ≥ 3 occurs that is not directly attributable to any treatment, subjects must fully recover or recover to CTCAE grade 1 within 7 days, with the following exceptions:

[0367] Alopecia of any CTCAE grade

[0368] Any other dermatological toxicity that resolved to CTCAE grade ≤ 2 within 2 weeks after the last dose and was treated with appropriate supportive care.

[0369] -CTCAE grade 3 fatigue that resolved to CTCAE grade ≤2 within 2 weeks of the last dose.

[0370] Grade 3 AEs of headache, insomnia, diarrhea, nausea, or vomiting that resolved to Grade ≤2 within 72 hours.

[0371] Any other non-hematologic or non-cardiac toxicity of CTCAE grade 3 or 4 that is grade ≤ 1 or has resolved by the next dose to the grade existing at study entry.

[0372] If oregovomab treatment is not tolerated after treatment interruption and infusion rate reduction with adequate supportive care, the subject will not receive further treatment with oregovomab, but may continue treatment with protocol-directed niraparib and be followed for survival.

[0373] Blinding This is not a blinded study.

[0374] Preparation / Handling / Storage / Accountability The Investigator or designee must ensure that proper temperature conditions are maintained for all study drug received, and any discrepancies must be reported and resolved prior to use of the study drug.

[0375] Only subjects enrolled in the study may receive the study treatment, and only authorized site staff may supply or administer the study treatment. Each study treatment must be stored in a secure, environmentally controlled (e.g., refrigerated), and monitored (manual or automated) location in accordance with the storage conditions listed on the label, with access restricted to the investigator and authorized site staff.

[0376] The Investigator (or site designee) will be responsible for study drug accountability, reconciliation, and record-keeping (e.g., recording of receipt, reconciliation, and final disposition).

[0377] Please refer to the Pharmacy Manual for instructions regarding preparation, administration, and disposal of study medication.

[0378] Study medication compliance Subject compliance with the study drug will be assessed at each visit. Deviations from the prescribed dosage regimen will be recorded by the investigator and / or study personnel at each site in the source and on the CRF.

[0379] Pre-emptive and concomitant treatments

[0380] Permitted Concomitant Therapies Any medicines or killed vaccines (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements) administered at the time of enrollment or during the study that are considered for the supportive care and safety of the subject must be recorded on the CRF with the reason for use, dates of administration including start and end dates, and administration information including dose and frequency. This includes, but is not limited to:

[0381] ·Medicines to prevent or treat nausea or vomiting.

[0382] Symptomatic treatment of tumor-related conditions, bone modifying agents and luteinizing hormone releasing hormone (LHRH) preparations

[0383] Antidiarrheal medication for subjects who develop diarrhea.

[0384] · Painkillers to make the subject as comfortable as possible.

[0385] ·Immunosuppressants to treat AEs suspected to be related to the immune response.

[0386] Medicines to treat chronic diseases (high blood pressure, high cholesterol, etc.).

[0387] Localized radiation therapy and bisphosphonate therapy for existing painful bone / liver metastases are permitted. Radiation therapy must be included on the CRF.

[0388] ·Oxygen therapy and blood products or transfusions.

[0389] Limited-field palliative radiation therapy is permitted as concomitant therapy. Local therapies administered during study drug administration should be documented on the CRF.

[0390] -Inactivated vaccines.

[0391] · Nutritional supplement or appetite stimulant

[0392] For oregovomab: Pre-infusion and post-infusion medications are permitted. Specifically:

[0393] Subjects who have experienced an infusion reaction to oregovomab during a previous infusion may be pretreated with a corticosteroid (e.g., dexamethasone), an antihistamine (e.g., diphenhydramine), and an H2 antagonist (e.g., cimetidine or ranitidine) at least 30 minutes prior to oregovomab in subsequent drug administrations.

[0394] Allergic reactions observed during and up to 2 hours after infusion may be treated with standard epinephrine, corticosteroids, and antihistamines per institutional guidelines.

[0395] For Niraparib: See Niraparib IB for more information. Subjects must inform the investigator of any new medicines taken after starting study drug. All medicines (other than study drug) and significant non-pharmacological therapies (including physical therapy, herbal / natural medicines, and blood transfusions) administered during the study must be listed on the CRF.

[0396] Concomitant medications other than those listed above may be considered on a case-by-case basis by the investigator in consultation with the medical monitor, if necessary.

[0397] Prohibited Concomitant Therapies or Therapies Require Caution Subjects may not use the investigational product or any of the therapies listed in the exclusion criteria concomitantly with the investigational product. Because certain drugs may inhibit the immunological mechanisms mediating the effects of the investigational product, it is recommended that subjects not receive the following medicines during treatment:

[0398] Contraindicated Therapies for Oregovomab:

[0399] Adrenocorticotropic hormone

[0400] Cyclosporine

[0401] Azathioprine

[0402] Live vaccines, such as yellow fever vaccine - from 28 days before the first dose of study drug to 90 days after the last dose of study drug

[0403] Strong CYP3A4 inhibitors (e.g., clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir)

[0404] Strong inducers of CYP3A4 or CYP2C8 (e.g., rifampicin, phenytoin, carbamazepine)

[0405] Biological and hormonal therapy

[0406] Nephrotoxic drugs

[0407] · Systemic administration of immunosuppressants (such as corticosteroids, methotrexate or immunosuppressant monoclonal antibodies) if chronically treated.

[0408] Within 30 days of Week 1, Day 1, or other investigational drugs being studied

[0409] Because certain drugs may inhibit the immunological mechanisms that mediate the effects of oregovomab, it is recommended that the following medicines not be administered during treatment:

[0410] The use of additional corticosteroids other than those used for chemotherapy premedication and hypersensitivity reactions (e.g., dexamethasone) during the acute phase should be avoided whenever possible, especially during administration of oregovomab, but may be used at the discretion of the treating physician.

[0411] Chronic systemic corticosteroids, prednisone or equivalent (e.g., dexamethasone, prednisone, etc.) for >5 days, except that inhaled or topically administered corticosteroids for the treatment of asthma are permitted.

[0412] Radiation therapy

[0413] Vitamin A

[0414] Antifungals (e.g., ketoconazole, miconazole)

[0415] Doxorubicin

[0416] Myelosuppressants

[0417] Aminoglycosides

[0418] Monoamine oxidase inhibitors (MAOIs) should be avoided if possible because they may interact with antihypertensive drugs (e.g., SC epinephrine) which may cause severe hypertension.

[0419] Subjects previously treated with chronic immunosuppressants must have discontinued treatment for at least 8 weeks prior to study initiation.

[0420] Prohibited or cautionary treatments for niraparib:

[0421] The following medicines are prohibited while undergoing protocol treatment:

[0422] Systemic anti-cancer or biologic therapy.

[0423] ·Immunotherapy.

[0424] ·Chemotherapy.

[0425] Investigational drugs other than niraparib and oregovomab

[0426] Radiation therapy involving >20% of bone marrow is prohibited within 2 weeks prior to and during study treatment day 1. Note: Small-field palliative radiation therapy may be permitted >1 week prior to study treatment day 1.

[0427] Surgery involving tumor involvement. Note: The administration of radiation therapy or surgery involving tumor involvement is considered progressive disease at the time of the procedure.

[0428] Niraparib is a weak inducer of cytochrome P450 (CYP) 1A2 in vitro and is a relatively poor substrate of P-glycoprotein (P-gp); therefore, investigators are encouraged to use with caution CYP1A2 substrates with narrow therapeutic ranges, i.e., theophylline and tizanidine.

[0429] Prophylactic cytokines (i.e., granulocyte-colony stimulating factor [GCSF]) should not be administered in the first cycle of the study but may be administered in subsequent cycles in accordance with current American Society of Clinical Oncology (ASCO) guidelines.

[0430] Rescue medication In this study, the Sponsor (or its designee) will not provide rescue medication as part of the study treatment.

[0431] Changes to antineoplastic therapy after 12 weeks and after 24 weeks, or uncontrolled disease progression The treating physician's clinical judgment should guide the management plan for each subject based on an individual benefit / risk assessment. Investigators should implement appropriate diagnostic and therapeutic measures and keep subjects under observation as long as medically indicated, in accordance with standard of care. The 12 weeks before the first radiographic evaluation is an immune priming period that may or may not include disease control activity with the experimental combination therapy. If disease control is not achieved, niraparib should be discontinued and the study subject should be instituted on deferred optimal next-line antineoplastic therapy. Final immunization will be performed for all patients at week 20.

[0432] Antineoplastic therapy may be initiated after the week 12 assessment and will be administered according to investigator best practice, with all information collected from weeks 12-24 after niraparib discontinuation along with start / end dates. Treatment initiated immediately after week 24 will also have its start date collected and followed up at follow-up. This may include any medications, radiation therapy, or surgery administered to the subject since discontinuing study drug. Patients with uncontrolled disease progression at any time during the protocol should be discontinued early from the protocol if indicated by the investigator's clinical judgment.

[0433] Exam assessment and procedures The testing procedures and timing are outlined in the Timings and Events Schedule, with "x" indicating when the assessment will take place.

[0434] No exemptions or variances to the protocol will be granted. If an urgent safety concern arises or is identified, a decision must be made immediately, in consultation with the sponsor, as to whether the subject should continue or discontinue study drug.

[0435] It is expected that all data obtained from these assessments, as described in the Timing and Event Schedule, must be supported by subject source documentation.

[0436] The available time slots for visits are as follows:

[0437] There are no appointment slots available on the first day of the first week.

[0438] · Unless otherwise stated, a typical time frame of ±3 days is allowed for evaluation to take into account public holidays.

[0439] · Image evaluation must be conducted at the times and as stated in the event schedule.

[0440] Pre-treatment procedures and evaluations Platinum-sensitive recurrent ovarian cancer subjects will be screened for eligibility during the 28-day period prior to Week 1, Day 1. During this period, inclusion and exclusion criteria will be assessed and all screening evaluations, laboratory tests, and procedures will be performed as described herein.

[0441] The results of all screening / baseline assessments must be reviewed by the investigator or his / her designee prior to enrolling the subject in the study to ensure that all inclusion and exclusion criteria have been met. All study subjects must be fully informed about all aspects of the study, including the study drug, visit schedule, required evaluations, and all regulatory requirements regarding informed consent.

[0442] The clinical laboratory assessments used to determine eligibility may be re-evaluated within the screening period if the screening results are outside the established ranges before the subject failed screening. If the re-test results meet the criteria, they may be used to determine eligibility. If the re-test results do not meet the criteria, the subject is considered to have failed screening.

[0443] Imaging evaluations already completed at the subject's routine examination within 28 days prior to the start of study treatment may be considered as baseline images for this study.

[0444] The list of procedures to be performed at screening is outlined in the Timing and Events Schedule.

[0445] Informed consent and participation confirmation

[0446] Potentially eligible subjects will be assessed for participation and asked to sign an informed consent form (ICF) prior to screening to ensure they meet all inclusion and exclusion criteria.

[0447] If a subject is determined to be eligible to enroll in the study, a patient enrollment form will be completed and sent to OncoQuest Pharmaceuticals, Inc. or its designee. OncoQuest Pharmaceuticals, Inc. or its designee will assign a subject number. Once assigned, subject numbers should not be reused for other subjects, and an individual's subject number should not be changed, even if the subject is rescreened. If a subject fails to enroll or begin treatment for any reason, the reason will be documented on the Screen Failure CRF.

[0448] Subject Demographics Data collected during screening may include, but is not limited to:

[0449] Sex / gender at birth

[0450] Date of birth (age or year of birth only if required by local regulations)

[0451] Race and ethnicity (if available)

[0452] Subject's initials (if collection is permitted by local regulations)

[0453] Medical history A complete medical history will be collected at screening and will include any significant medical, surgical, and allergic illnesses that may affect the subject's evaluation / current medical condition (e.g., all relevant current medical conditions present at the time of signing informed consent).

[0454] The medical history should include details regarding the initial diagnosis and extent of ovarian cancer, including but not limited to date of disease diagnosis, staging at time of initial diagnosis, histology / cytology, histological grade, sites of metastasis, and primary site of cancer.

[0455] Medications taken for a medical condition other than active cancer must be recorded on the Concomitant Medications CRF.

[0456] All previous surgeries, the reason and details, date of surgery and the outcome of surgery will be recorded.

[0457] History of relevant cancer For each subject, relevant cancer medical history must be recorded on the CRF and may include, but is not limited to:

[0458] Primary site of cancer

[0459] Staging Systems

[0460] Staging at initial diagnosis and study entry

[0461] Date of first recurrence / progression

[0462] Most recent recurrence / progression

[0463] Histological grade

[0464] ·Predominant tissue diagnosis / cytology

[0465] The presence or absence of metastatic sites (if any, their location).

[0466] FIGO Staging The FIGO staging system is a classification system for ovarian cancer established by the International Federation of Gynecology and Obstetrics (Berek et al., 2018). For details, see Appendix B. FIGO staging will be recorded on the subject's CRF.

[0467] FIGO stage will be recorded at screening and before the first dose of study treatment.

[0468] NOTE: To be included in this study, eligible subjects must have FIGO stage III or IV disease.

[0469] History of anti-cancer drug treatment All prior anti-cancer treatments must be recorded on the appropriate CRF, including surgical interventions (including cytoreductive surgery, whether optimal or suboptimal, primary or intermediate) and chemotherapy, biological therapy, immunotherapy, and radiation therapy (including prior PARP inhibitors) provided for the treatment of cancer prior to administration of study drug.

[0470] There are no restrictions on use of prior PARP inhibitor therapy.

[0471] BRCA1, BRCA2 and HRD status At screening time, past samples of BRCA1, BRCA2 mutations and HRD status must be collected from the subject's medical history and recorded on the appropriate CRF page.

[0472] Other baseline assessments Additional screening / baseline assessments will be conducted according to the respective timing and event schedule (Appendix A), including but not limited to:

[0473] 1.β-HCG test

[0474] 2.Medication history and concomitant medications

[0475] 3. CA-125

[0476] Safety assessment Any significant findings that were present prior to signing of informed consent must be noted on the Medical History page of the subject's CRF. Any significant new findings that began or worsened after informed consent must be recorded on the Adverse Events page of the subject's CRF.

[0477] Vital signs Vital signs (heart rate [beats per minute], blood pressure [systolic and diastolic] measured in a seated position after at least 3 minutes of rest, respiratory rate [per minute], and temperature [degrees Celsius]) will be recorded within 30 minutes of starting oregovomab infusion and within 1 hour after discontinuing infusion at the end of oregovomab infusion. On days when oregovomab is not being administered at the visit, vital signs will be measured according to facility standards.

[0478] Height (cm) will be measured at screening only.

[0479] Body weight (in kilograms) in house clothing and without shoes will be measured at screening and at subsequent time points as specified in the timing and event schedule.

[0480] Physical Examination Physical examinations will be performed to assess the effects of study drug administration. At selected visits, physical examinations will be performed according to the schedule outlined in the Timing and Events Schedule.

[0481] The head and neck, eyes, ear, nose and throat (EENT), cardiac, respiratory, abdominal, extremities, pelvis, skin and lymph nodes should be evaluated for normal or abnormal findings, with a description and severity of any abnormalities noted.

[0482] ECOG Performance status will be assessed according to the ECOG performance status scale (Oken et al., 1982) according to the schedule described in the Timing and Events Schedule.

[0483] [Table 11]

[0484] Lab Test All clinical laboratory evaluations listed in Table 8 will be performed on-site and will be conducted according to the Timing and Events Schedule. The on-site laboratory will be used to qualify subjects for study entry or if safety concerns arise during the study.

[0485] If post-baseline laboratory values ​​are deemed clinically significant, they will be assessed by the investigator for a causal relationship to study drug administration and medically appropriate treatment will be administered. Subjects experiencing adverse events will be monitored until all symptoms have resolved. Abnormal laboratory values ​​will also be staged according to CTCAE v5.0. Abnormal values ​​will be recorded on the CRF. Laboratory values ​​outside the normal range and significantly different from baseline values ​​will be repeated as necessary until the abnormality has resolved or an etiology has been identified to the investigator's satisfaction.

[0486] Unscheduled laboratory evaluations may be performed on-site to document (potential) adverse events or as medically indicated for decision making (e.g., disease progression). On-site laboratory specimens will be collected and analyzed according to site requirements. Values ​​and normal ranges should be provided on the local laboratory CRF.

[0487] [Table 12]

[0488] Pregnancy and fertility evaluation Pregnancy testing is not required for subjects determined to be postmenopausal. Women are considered postmenopausal and of no childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age-appropriate history of vasomotor symptoms) or have undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to the start of study treatment. In the case of oophorectomy alone, a woman will only be considered of no childbearing potential if follow-up hormone evaluation confirms her reproductive status.

[0489] For females of childbearing potential, a serum pregnancy test (β-HCG) must be completed within 7 days prior to the first dose of study treatment and at the end of treatment. Urine pregnancy tests will be performed throughout the treatment period as indicated in the Timing and Events Schedule. If a subject becomes pregnant during the treatment period, study treatment must be discontinued.

[0490] Male partners of participating women of childbearing potential must use condoms during sexual intercourse while the female partner is receiving the study treatment and for at least 30 days after the female partner stops taking the study treatment.

[0491] 12-lead electrocardiogram Standard 12-lead electrocardiograms (ECGs) will be performed in the supine position for at least 5 minutes at screening, end of week 12, and end of week 24, per site guidelines. If a subject is discontinued before reaching week 24, an ECG will be performed at the EOT visit. Interpretation of the waveforms must be performed by a qualified physician and recorded on the subject's ECG eCRF page. Each ECG waveform will be labeled with the study number, subject initials (if regulations permit), subject number, and date, and will be retained as study site source documentation.

[0492] Imaging Test Imaging evaluation (CT / MRI) and radiographic reports will be collected for disease assessment and will be performed at baseline, week 12, and week 24 visits using RECIST v1.1. Subsequent imaging evaluations will be performed according to institutional guidelines. Subjects will be treated until end of treatment at week 24, discontinuation due to disease progression, loss to follow-up, withdrawal of consent, treatment with another anticancer agent, or death.

[0493] Pharmacodynamic and biomarker evaluation No pharmacodynamic measurements will be performed in this study. All biomarker assessments described are exploratory.

[0494] [Table 13]

[0495] Early humoral immune response Early humoral immune response will be assessed by measuring HAMA at the time points specified in the Timing and Events Schedule (Appendix A). Serum samples will be collected, processed, and measured for HAMA at the study site and sent to the reference laboratory as directed in the test manual. Early humoral response is defined as an increase from baseline to >74 ng / ml. This ratio will also be calculated from the ratio of week 7 to baseline samples.

[0496] CA-125 Blood samples for assessment of CA-125 will be collected according to the timing and event schedule (Appendix A).

[0497] Treatment of subjects with the anti-CA-125 murine antibody B43.13 (oregovomab) may lead to false elevations or declines in CA-125 values, depending on the assay used to perform the test during the treatment period. Therefore, CA-125 measurements should not be performed within 15 days after oregovomab infusion. Similarly, the potential presence of HAMA may interfere with CA-125 measurements, as some commercially available CA-125 assays compete with the detection antibody. Therefore, CA-125 measurements are performed using an assay that is not sensitive to the presence of HAMA (Abbott Architect i1000SR or equivalent).

[0498] NMLR as a prognostic factor Neutrophil plus monocyte and lymphocyte ratios (with differences) calculated from baseline pretreatment complete blood counts are associated with clinical outcomes.

[0499] Samples for future evaluation of changes in cellular immunity Each patient will have 20 mL of whole blood drawn at baseline, week 12, and week 24 and shipped by express to a central immunology laboratory using the kit provided, following the instructions in the laboratory manual. These samples will be cryopreserved at the central laboratory for the isolation of PBMCs and future evaluation of antigen-specific cellular immunity and immunophototyping.

[0500] Pharmacokinetics PK will not be collected in this study.

[0501] Efficacy evaluation Tumor assessment Disease control rates (DCR) defined as CR, PR, or SD will be determined by the investigator at weeks 12 and 24 according to RECIST v1.1 (EA Eisenhauer et al., EJC 45 (2009) 228-247). The same assessment methods and the same techniques will be used for characterization of individual and reported lesions at baseline and during follow-up.

[0502] Assessment of disease progression Disease progression will be assessed locally according to RECIST v1.1 at weeks 12 and 24. Response to second-line treatment at week 24 will be compared with week 12 and baseline (EA Eisenhauer et al., EJC 45 (2009) 228-247). Decisions regarding subject management will be made by the local investigator.

[0503] The diagnosis of possible progression is made on the basis of imaging or other objective clinical findings, which may include palpable disease, evidence of new or worsening pleural or ascites effusion requiring histologic confirmation, pelvic and / or abdominal pain, or other multisystem symptoms, preferably confirmed by imaging.

[0504] The date of definitive disease progression is used to calculate PFS. If unscheduled imaging is performed to confirm response or if disease progression is suspected, subsequent imaging will be performed according to the original imaging schedule.

[0505] Exploratory Efficacy Endpoints and Analytical Measures The following exploratory tumor response measures with selected interim clinical endpoints will be performed: PFS, TFST and overall response rate (ORR) (for second-line chemotherapy, determined by CR and PR at week 24 compared to week 12). CA-125 testing will also be performed in conjunction with exploratory efficacy endpoint measures.

[0506] Missed visits Every effort will be made to maintain the integrity of study visits by adhering to the original visit schedule, including all necessary tests and evaluations. Missed visits must be rescheduled as soon as possible, provided that the rescheduled visit is not within 2 weeks of the next scheduled visit, in which case the missed visit will not be completed and the next visit will occur at the originally scheduled time. All study visits will be scheduled based on the treatment schedule.

[0507] Temporary or permanent discontinuation of study medication Oregovomab In rare cases, it may be necessary for a subject to permanently discontinue study treatment. If study treatment is permanently discontinued, the subject will remain in the study to be evaluated for safety, post-treatment efficacy follow-up in the absence of disease progression, and survival, unless consent is withdrawn or the subject is lost to follow-up.

[0508] If a subject decides to discontinue study treatment, the investigator will make reasonable efforts (e.g., phone call, email, letter) to understand the primary reason and record that information in the subject's medical record and on the appropriate CRF page. Discontinuation can be considered if they express an intention to discontinue, miss a clinic visit, or are lost to follow-up for any other reason.

[0509] The investigator should discontinue study treatment for a subject if he or she considers that continuation would be harmful to the subject's health.

[0510] The following are possible reasons for discontinuing study treatment:

[0511] 1.Disease progression documented before week 12.

[0512] 2. Use of another investigational or commercially available anticancer agent prior to documented disease progression.

[0513] 3. Occurrence of serious or intolerable adverse events requiring discontinuation at the discretion of the investigator.

[0514] 4. Loss to Follow-Up. Sites must contact the subject and attempt to reschedule any missed visits as soon as possible, counsel the subject on the importance of maintaining the assigned visit schedule, and confirm whether the subject wishes and / or should continue in the study.

[0515] 5. Investigator's discretion. If the investigator determines that continued participation would be detrimental to the subject's health.

[0516] 6. Any deviation from the protocol that, in the opinion of the sponsor and investigator, justifies discontinuation of the trial.

[0517] 7. Subject is not adhering to the terms of the protocol.

[0518] 8. Cancellation of the Study by the Sponsor

[0519] Subjects who permanently discontinue both study drugs during the Treatment Period will be scheduled for an EOT, or Treatment Exit Visit, within 14 days of the date study drugs are permanently discontinued, at which time all assessments described in the Timing and Events Schedule (Appendix A) will be performed.

[0520] Subjects who discontinue the post-treatment follow-up period for any reason will not complete any follow-up assessments and will be followed up for survival only.

[0521] Niraparib Subjects may continue protocol treatment with niraparib for up to 24 weeks or until any of the following criteria is met:

[0522] 1.Disease progression

[0523] 2. Serious or life-threatening adverse events

[0524] 3. Significant non-compliance with the protocol as determined by the investigator and / or sponsor

[0525] 4. Decision to withdraw from the study

[0526] 5. If the subject becomes pregnant

[0527] 6. Subject has been diagnosed with MDS or AML (as confirmed by a hematologist)

[0528] 7. The Investigator, Sponsor and / or TESARO becomes aware of any situation or event that suggests a possible risk or danger to the subject if the subject continues in the clinical trial.

[0529] Withdrawal of subjects from the study If a subject permanently discontinues study medication, the subject will participate in 30-day follow-up and subsequent survival follow-up unless consent is withdrawn from the study altogether or the subject is lost to follow-up.

[0530] Subjects must be withdrawn from the study drug if any of the following apply:

[0531] ·pregnancy

[0532] ·death

[0533] Withdrawal of consent

[0534] If a subject withdraws consent for future disclosures, Sponsor may retain and continue to use data collected prior to such withdrawal of consent.

[0535] If a subject withdraws from the study, the subject may request that any samples collected but not tested be destroyed, and the investigator must document this in the site's study records.

[0536] Subjects who discontinue the study after the first dose of study drug will be considered for safety analyses, at a minimum. Discontinued subjects will not be replaced.

[0537] Subjects are considered lost to follow-up if they fail to attend multiple scheduled visits and cannot be contacted by the study site.

[0538] If a subject fails to return to the clinic for a required study visit, the following actions must be taken:

[0539] Sites must contact subjects and attempt to reschedule any missed visits as soon as possible, counsel subjects on the importance of maintaining their assigned visit schedule, and determine whether the subject wishes and / or should continue in the study.

[0540] Before a subject is considered lost to follow-up, the investigator or designee must make every effort to re-establish contact with the subject (three telephone calls, if possible, and, if necessary, a certified letter or equivalent separate method sent to the subject's last known mailing address). These contact attempts must be documented in the subject's medical record.

[0541] If a subject continues to be unable to be contacted, he or she will be considered to have withdrawn from the study.

[0542] Safety Management, Monitoring and Reporting AE definition Adverse Event means any medical occurrence in a human subject or clinical trial subject that is medically untoward and temporarily related to the use of an investigational intervention, whether or not considered related to the investigational intervention.

[0543] NOTE: Thus, an AE refers to any untoward and unintended sign (including laboratory abnormalities), symptom, or disease (new or worsening) that is temporarily associated with the use of the study intervention.

[0544] Adverse events that meet the definition of AE Any abnormal clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., electrocardiogram, radiology scan, vital sign measurements) that are deemed clinically significant (unrelated to progression of the underlying disease) in the medical and scientific judgment of the investigator (including deterioration from baseline).

[0545] · Chronic or intermittent exacerbation of a pre-existing condition (including either an increase in the frequency and / or intensity of symptoms).

[0546] ·Diseases that may have been present before the start of the study but are newly discovered or diagnosed after administration of the study drug.

[0547] · Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction.

[0548] Signs, symptoms, or clinical sequelae of a suspected overdose of the study or concomitant medication. Overdoses themselves are not reported as AEs / SAEs unless they are intentional overdoses with possible suicidal / self-harming intent. Such overdoses must be reported regardless of the presence or absence of sequelae.

[0549] "Lack of efficacy" or "failure to achieve the expected pharmacological effect" itself is not reported as an AE or SAE. Such cases are included in the efficacy evaluation. However, signs, symptoms, and / or clinical sequelae attributable to lack of efficacy are reported as AEs or SAEs if they meet the definition of an AE or SAE.

[0550] Adverse events not meeting the definition of AE Clinically significant laboratory abnormalities of Grade 3 or 4 per CTCAE v5.0, or other safety abnormalities related to the underlying disease, unless the investigator determines that the abnormalities are more severe than would be expected for the subject's condition.

[0551] The disease / disorder being studied, or the expected progression, signs or symptoms of the disease / disorder being studied, unless they are more severe than expected for the subject's condition.

[0552] Medical or surgical procedure (e.g., cytoreduction, endoscopy, appendectomy): The condition leading to the procedure is an AE.

[0553] · Situations where no medically harmful events occurred (social and / or convenience hospitalization).

[0554] · Expected and non-worsening day-to-day variations in pre-existing conditions or diseases present or detected at the start of the study.

[0555] Serious Adverse Events Definition of serious adverse events If an event is not an AE according to the above definition, it is not an SAE even if it meets the serious criteria (eg, hospitalization due to signs / symptoms of the disease under study, death due to disease progression).

[0556] SAEs are defined as any medically untoward occurrence, regardless of dose:

[0557] A. It causes death.

[0558] B. lethal

[0559] The term "life-threatening" in the definition of "serious" refers to an event that was at risk of causing death to the subject at the time of its occurrence, not an event that, if more severe, might have caused death.

[0560] C. Hospitalization is required or an existing hospitalization needs to be extended.

[0561] In general, hospitalization means that a subject was admitted to a hospital or emergency room for observation and / or treatment that is not appropriate in a physician's office or outpatient setting (usually involving at least an overnight stay in the hospital). A complication that occurs during hospitalization is an AE. An event is serious if the complication prolongs the hospital stay or meets other serious criteria. If there is any doubt as to whether a "hospitalization" occurred or was necessary, the AE should be considered serious.

[0562] Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

[0563] D. Causes lasting impairment / disability

[0564] The term disability means a significant impairment in the ability to carry out normal life functions.

[0565] This definition does not include relatively medically minor experiences such as uncomplicated headache, nausea, vomiting, diarrhea, flu, and accidental trauma (e.g., sprained ankle), which may interfere with or prevent functioning of daily life but do not significantly impair it.

[0566] E. Congenital Anomalies / Birth Defects

[0567] F. Other Conditions (Major Medical Events):

[0568] Medical or scientific judgment should be used in determining whether SAE reporting is appropriate in other situations, such as medically significant events that are not immediately life-threatening or result in death or hospitalization, but that may endanger the subject or require medical or surgical intervention to prevent any of the other outcomes listed in the definition above. These events should generally be considered serious.

[0569] Examples of such events include invasive or malignant cancer, intensive care in an emergency room or at home for allergic bronchospasm, blood disorders or seizures that do not result in hospitalization, or the onset of drug addiction or abuse.

[0570] SAEs will be collected during the screening period of the study, regardless of whether the study intervention was administered at the time the ICF form was completed. SAEs will be recorded on a form provided by the sponsor (or its designee). SAEs occurring more than 30 days after the last dose of study treatment should be reported to the sponsor (or its designee) only if the investigator determines that the SAE is related to the study treatment.

[0571] Subject death If a subject dies after signing informed consent to participate in the study and within 30 days after receiving the last study treatment, this must be reported to the sponsor.

[0572] Deaths from any cause occurring within 30 days after the last dose of study treatment may be recorded as SAEs but will not be promptly reported to regulatory authorities unless requested. Subject deaths occurring during the survival follow-up period will also be recorded in support of the overall survival objective of the study.

[0573] Adverse events of particular interest Adverse Events of Special Interest (AESI) are defined as events (serious or non-serious) of scientific and medical concern specific to the sponsor's product or program that warrant ongoing monitoring by the investigator and prompt communication to the sponsor. These AE terms include, but are not limited to, the following: hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, generalized urticaria, infusion reactions, injection site reactions, and others identified through ongoing review of the data. Further investigation may be required to characterize and understand such events.

[0574] Recording and follow-up of AEs and / or SAEs AE and SAE records If an AE / SAE occurs, it is the investigator's responsibility to review all documentation related to the event (e.g., hospital progress notes, laboratory and diagnostic reports).

[0575] -Investigators will record all relevant AE / SAE information on the CRF.

[0576] Investigators are not permitted to send copies of subject medical records to OncoQuest Pharmaceuticals (or their designee) in lieu of completing the AE CRF page.

[0577] Copies of medical records for specific cases may be requested by OncoQuest Pharmaceuticals (or designee), in which case all subject identifiers, except for the subject number, will be redacted from copies of the medical records prior to submission to OncoQuest Pharmaceuticals (or designee).

[0578] · Investigators will attempt to establish a diagnosis of the event based on signs, symptoms, and / or other clinical information. Whenever possible, the diagnosis (not individual signs / symptoms) will be recorded as the AE / SAE.

[0579] Severity assessment Investigators will perform a severity assessment of each AE and SAE reported during the study according to CTCAE v5.0. It is important to distinguish between serious and nonserious AEs. Severity is a measure of intensity, and severity is defined by the criteria detailed herein. Severe AEs are not necessarily considered serious.

[0580] Causal assessment The investigator is obligated to assess the relationship between the study intervention and the occurrence of each AE / SAE. A "reasonable possibility" of relationship means that there is fact, evidence, and / or reason to suggest a causal relationship, rather than that a relationship cannot be ruled out. The investigator will use clinical judgment to determine the relationship. Alternative causes, such as underlying disease, concomitant medications, and other risk factors, as well as the temporal relationship of the event to the administration of the study intervention, will also be considered and investigated. The investigator will also refer to the product information for the IB and / or marketed products in their evaluation.

[0581] For each AE / SAE, the investigator must document in the medical note that the AE / SAE has been reviewed and an assessment of causality has been made. There may be cases where an SAE occurs and the investigator has only minimal information to include in the initial report to OncoQuest Pharmaceuticals (or its designee). However, the investigator is required to provide a causality assessment for all events at the time of the initial submission of SAE data to the sponsor (or its designee). The investigator may change his or her opinion of causality in light of follow-up information and submit an SAE follow-up report with an updated causality assessment. The causality assessment is one of the criteria used to determine regulatory reporting requirements.

[0582] The following definitions (Table 9) should be considered when evaluating the relationship of AEs and SAEs to study interventions.

[0583] [Table 14]

[0584] Assessing predictability The Sponsor's Medical Monitor (or designee) is responsible for determining whether an AE or SAE is expected or unexpected. An AE or SAE is considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously described in the IB for the study intervention. The final determination of whether an AE or SAE is expected or unexpected rests with the Sponsor's Medical Monitor (or designee).

[0585] Follow-up of AEs and SAEs The Investigator is obligated to perform or arrange for any supplemental measurements and / or evaluations medically indicated or requested by OncoQuest Pharmaceuticals, Inc. (or its designee) to elucidate as completely as possible the nature and / or causality of any AE or SAE, which may include additional clinical tests or investigations, histopathological examinations, or consultations with other medical professionals.

[0586] If a subject dies during the study or permitted follow-up period, the Investigator will provide OncoQuest Pharmaceuticals (or its designee) with a copy of the postmortem findings, including histopathology.

[0587] Any new or updated information will be recorded on the CRF where it was originally completed.

[0588] The investigator will submit updated SAE data to OncoQuest Pharmaceuticals within 24 hours of receiving the information.

[0589] SAE Reporting All SAEs must be reported to the Sponsor's designee within 24 hours of first becoming aware of them by the investigator and the designated pharmacovigilance team, as described in the SAE report.

[0590] An SAE report must be completed for any SAE, including death from any cause or of unknown cause, including those described in the protocol or IB, whether or not considered study-related, and includes an evaluation of whether the event was reasonably likely to have been caused by the study intervention. Investigators will report all SAEs that occur after signing the ICF, during the study treatment period, or within 30 days after the last dose of study intervention. SAEs occurring more than 30 days after the last dose should be reported to the sponsor (or its designee) only if the investigator suspects a causal relationship to the study treatment.

[0591] Follow-up of SAEs will be reported in the same manner as the initial SAE report, within 24 hours of the investigator receiving the follow-up information. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode, regardless of when it occurred. Follow-up information should describe whether the event resolved or continued, whether and how it was treated, and whether the subject continued or withdrew from the study. SAEs that occur at different time intervals, or that are considered completely unrelated to those previously reported, must be reported separately as new events.

[0592] All SAEs will be followed up until satisfactory resolution or until the site investigator determines that the event has become chronic or the subject's condition is stable; this includes subjects who may be excluded due to a serious or unexpected adverse event. Other documentation supporting the event may be required by the Sponsor (or its designee) and must be provided as soon as possible.

[0593] If the SAE has not been recorded in the IB for any of the study drugs and is thought to be related to the study drug, the sponsor's medical monitor (or designee) may urgently request further information from the investigator for reporting to health authorities. The sponsor (or its designee) may be required to issue an "Investigator Notification Letter" to inform all investigators involved in studies with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the FDA.

[0594] Pregnancy Report All pregnancies must be reported to the sponsor's designee via a pregnancy report form within 24 hours of the investigator and / or his / her staff first becoming aware of the pregnancy. Subjects who test positive for pregnancy after signing the ICF must discontinue the study intervention and be immediately withdrawn from the study. Investigators will report all pregnancies that occur after signing the ICF, during the study treatment period, or within 30 days after the last dose of study intervention. Pregnancy itself is not considered an AE. Pregnancy is considered an SAE if the mother and / or products of conception die, if the pregnancy itself causes hospitalization or an extension of a preexisting hospitalization, or if the newborn infant has a congenital anomaly or birth defect.

[0595] The Investigator must follow up the status of the pregnancy to determine pregnancy outcome (including early termination) and maternal and fetal status. Pregnancy follow-up information must be reported to the Sponsor's designee within 24 hours of awareness of the pregnancy. Pregnancy complications, spontaneous abortions, and / or elective terminations for medical reasons must also be reported. When reported, the possibility of an association with the study drug must be assessed.

[0596] If additional information becomes available, it must be promptly reported through the same contacts listed above, including all new information in the Pregnancy Report. Additional information may be requested by the Sponsor's designee, as necessary.

[0597] Data Safety Monitoring Committee This trial will not have a formal Data Safety Monitoring Board (DSMB).

[0598] Safety Data Review Committee A Safety Data Review Committee (SDRC) consisting of investigators and representatives of the sponsor will be established to monitor safety during the trial. Based on available safety information from subjects, the SDRC will make recommendations to the sponsor regarding continuing, modifying or discontinuing the trial. The final decision to interrupt, modify or terminate the trial rests with the sponsor. The SDRC will be governed by a separate charter.

[0599] statistical methods Details of the statistical methods for this study will be described in the Statistical Analysis Plan (SAP).

[0600] Determining sample size A sample size of 10 subjects is estimated to provide a sufficient initial descriptive evaluation of safety interactions related to the combination therapy and to provide preliminary evidence of clinical and immune response patterns. The study should also provide signals that allow for extrapolation of future study designs. The sponsor may enroll up to 30 additional subjects for further evaluation in the study after reviewing the available safety and efficacy data for the subjects.

[0601] Enrollment of additional subjects will be determined based on the following considerations:

[0602] Increased early humoral response to infused antibodies: ≥60% at week 7 (~DAY42);

[0603] Disease control rate (DCR): 40% CR / PR / SD at 12 weeks.

[0604] Analysis population The intention-to-treat (ITT) analysis population will include all enrolled subjects (defined as subjects who received at least one dose of both study drugs) and will serve as the primary analysis population for all efficacy endpoints and demographics.

[0605] The per-protocol (PP) population includes all subjects who have baseline and post-baseline efficacy measurements, have received at least three infusions of oregovomab, and have no significant protocol violations that could affect efficacy evaluations. The PP population will be used as a supportive population for efficacy endpoints.

[0606] The safety population will include all subjects who received any dose of study drug (niraparib or oregovomab) and will be the primary analysis population for safety endpoints.

[0607] Procedures for dealing with missing, unused and fake data Other than as described in this section, no imputation of missing data will be performed. Details regarding the handling of missing data will be described in the statistical analysis plan.

[0608] For DCR, subjects who do not have a 12-week efficacy assessment will be considered censored at time 0. Additional censoring details will be described in the statistical analysis plan.

[0609] For AEs, missing or partial dates are handled as follows in determining treatment initiation: If partial dates are available, they are used to assess whether the AE occurred during the treatment period. AEs with completely missing start and end dates are presumed to be treatment initiation.

[0610] Missing AE severity was not entered and was considered missing in the tabulation of severity. For AEs with missing answers to questions regarding relatedness to treatment, the event was considered related.

[0611] Common methods Baseline demographics, disease characteristics, safety parameters, and laboratory data will be tabulated using descriptive statistics (mean, standard deviation, median, minimum, maximum) for continuous variables and frequency counts and percentages for discrete variables. Kaplan-Meier estimation will be used to estimate summary statistics for PFS, DOR, and OS. The 25th, 50th (median), and 75th percentiles with associated two-sided 95% confidence intervals, and the proportion of censored subjects will be presented. All data will be provided in tables. All statistical analyses will be performed using SAS version 9.4 or later. No formal statistical tests will be performed.

[0612] Analysis time point The interim analysis will be performed once at least 10 evaluable subjects have completed the Week 12 visit. To be included in the interim analysis population, the following criteria must be met:

[0613] Participants must have received at least three doses of oregovomab and have at least 80% compliance with niraparib dosing.

[0614] Subjects must have data available on early humoral immune responses (screening and at least one post-treatment sample) at week 7.

[0615] Subjects must have completed at least two imaging evaluations.

[0616] Up to 5 subjects will be replaced if they do not meet the above criteria. Subjects who have received at least one dose of any study drug will not be replaced. Subjects who are screened but have not received any study drug may be replaced.

[0617] DCR and ORR analyses will occur after the last subject has attended the Week 24 visit and 30-day safety follow-up visit (LPLV). Final analyses will be completed and the Final Clinical Trial Report (CSR) completed after the last subject has completed the treatment period. The sponsor reserves the option to prepare a CSR addendum that takes into account long-term survival data, if available.

[0618] statistical analysis Disposition, demographics and baseline characteristics Tables will be presented of subject disposition, including numbers in each analysis set, numbers lost to follow-up, numbers discontinued before study completion, and reasons for discontinuation.

[0619] Demographic and baseline characteristics will be summarized descriptively. Data assessed include age, race, medical history, and prior treatment history. No formal statistical comparisons will be made.

[0620] Efficacy analysis Preliminary assessments of antitumor activity of this combination include disease control rate (CR / PR and SD) and PFS. Disease control rate (CR, PR or SD) and best overall response rate (BOR) will be determined at weeks 12 and 24. BOR is defined as the best documented assessment of CR and PR from treatment initiation until progression / recurrence as defined by RECIST 1.1. Data listings will include responses at each time point and treatments administered beyond week 12. DCR in subjects who received second-line chemotherapy beyond week 12 will be additionally exploratory assessed, with week 12 as the baseline assessment, and will be described separately.

[0621] Progression-free survival is measured from the date of first study treatment to the earliest date of disease progression or death as determined by the local radiologist / investigator. Subjects without documented progression and alive prior to analysis will be censored at the date of last complete disease assessment per RECIST v1.1 (or prior to 2 or more missed assessments, if applicable). PFS will be described for all subjects. Tumor assessments must be performed as scheduled regardless of delays or interruptions of study treatment.

[0622] Overall survival will be calculated from the date of first study drug administration to the date of death. Subjects who are still alive at the time of analysis or who dropped out before the end of the study will be censored at the date of their last confirmed survival.

[0623] Analysis of exploratory markers of activity Exploratory markers are listed in the SAP. Baseline NMLR, a prognostic factor, is correlated with clinical endpoints.

[0624] Early humoral immune response analysis The early humoral response to the infused antibodies is assessed using a human anti-mouse antibody kit. Baseline values ​​and all subsequent time points are compiled and tabulated. In addition, the incidence of patients with an increase in HAMA >74 ng / mL relative to baseline is calculated. The ratio of the week 7 value to the baseline value, the early humoral response ratio (EHRR), is also calculated for each patient and correlated with clinical parameters.

[0625] Cellular immune response analysis Future samples will be stored in a tissue bank to assess tumor-specific cellular immunity and immune phenotype; however, no analysis of this data is planned in the primary analysis and summary report of this study. Future supplemental reports and analyses will be generated upon completion of these exploratory studies.

[0626] Safety analysis Safety will be assessed by treatment-emergent adverse events (TEAEs) per CTCAE v5.0, physical examination, laboratory tests, and vital signs.

[0627] Adverse events Adverse events will be coded using MedDRA version 22 or higher for summarization and displayed in tables and listings using system organ class (SOC) and preferred terms.

[0628] Analysis of AEs was performed for events considered treatment-emergent, defined as AEs that occurred between the first and last dose of treatment and within 30 days after the last dose, or that the investigator considered to be drug-related, or that were present at baseline but worsened in intensity.

[0629] Adverse events are tabulated at subject incidence so that in any tabulation a subject contributes only once to the calculation for a given AE (preferred term). Separate tabulations will be performed for serious adverse events (SAEs), adverse events leading to discontinuation, adverse events assessed by the investigator as possibly, probably, or definitely drug related, and serious adverse events of at least CTCAE grade 3. Infusion-related reactions (IRRs), hypersensitivity reactions (HSRs), and adverse events of special interest (AESIs) will also be tabulated. The AE terms used for AESIs will be provided in the SAP.

[0630] No formal hypothesis testing regarding AE incidence will be performed.

[0631] Adverse events of special interest (AESIs) will require ongoing monitoring and prompt communication by the Investigator to the Sponsor. The term AESIs includes, but is not limited to, the following: hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, generalized urticaria, infusion reactions, injection site reactions, and others identified through ongoing review of the data.

[0632] All AEs (treatment initiation and post-treatment) will be documented in the subject data listing. The following will be documented separately: subject deaths, AESIs, SAEs, and AEs leading to treatment discontinuation.

[0633] Study drug exposure Study drug exposure for oregovomab and niraparib will be summarized, including the number of doses of each drug, the number of dose reductions or withholdings / discontinuations, and total study drug exposure (calculated as (date of last dose of any study drug – date of first dose of any study drug + 1) / 30.4375).

[0634] Laboratory Values, Vital Signs, and Physical Examination Laboratory values ​​are expressed using conventional SI units. Severity of selected laboratory measurements is determined using CTCAE criteria (e.g., with corresponding CTCAE grading classifications). Shift tables are generated comparing changes from baseline to worst during the study with CTCAE classification ranges.

[0635] Laboratory and vital signs will be summarized as to actual values ​​and changes from baseline to each evaluation during the study. Additional safety measurements, including physical examinations, will be documented for each subject.

[0636] Concomitant medications Concomitant medications will be coded using the WHO Drug Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Class (ATC) and Preferred Term.

[0637] Concomitant medications will be tabulated, including any medications that were not discontinued prior to the first dose of the therapeutic agent. Medications are considered concomitant if the end date is unknown or if they are ongoing at the time of first dose.

[0638] Administrative requirements Standards for conducting clinical trials of pharmaceuticals OncoQuest Pharmaceuticals and the Investigator agree to adhere to the protocol by mutual consent. Any changes to this study must be agreed upon in writing by the Investigator and OncoQuest Pharmaceuticals prior to initiating the change.

[0639] The investigators also agree to conduct the trial in accordance with regulations of the U.S. Food and Drug Administration (FDA) and other relevant health authorities, as well as the principles of Good Clinical Practice (GCP).

[0640] Ethical considerations The study will not begin until all regulatory requirements have been met. The study will be conducted in accordance with the protocol, the most recent version of the Declaration of Helsinki, and the ICH Tripartite Guidelines for GCP adopted by the FDA in 1996.

[0641] Protocol Review The protocol must be reviewed and approved by the appropriate Institutional Review Board (IRB) / Independent Ethics Committee (IEC) where the study will be conducted. The Investigator is responsible for obtaining and maintaining IRB / IEC approval of the study (at least annually). Written approval from the IRB / IEC must be provided to OncoQuest Pharmaceuticals before release of the investigational product is permitted.

[0642] The Investigator will submit all changes, modifications, and revisions to OncoQuest Pharmaceuticals, Inc. or its designee, and the IRB / IEC. Changes to the protocol that affect subject selection, safety, or changes in the conduct of the study require written approval by OncoQuest Pharmaceuticals, Inc. and the IRB / IEC before the change is implemented. Changes to the protocol intended to eliminate a clear and imminent hazard may be implemented immediately, but the IRB / IEC must be notified.

[0643] Informed consent review Written informed consent is required for this study. If the subject is legally incompetent (i.e., a minor or mentally incompetent), written consent must be obtained from a parent, legal guardian, or legal representative and such consent must be witnessed.

[0644] The Investigator also hereby agrees that OncoQuest Pharmaceuticals and the IRB / IEC will approve the informed consent of all subjects prior to initiating the study. The Investigator or designee will obtain informed consent and document this process by noting the date and time of consent on the source document for all subjects enrolled in this study. Informed consent must be obtained prior to initiating any screening procedures related to this study.

[0645] The informed consent form will explain to the potential subject the nature, purpose, risks, and duration of the study. Subjects will be told who they will consult with about the study and what to do if they experience side effects during the study. The informed consent form will state that representatives of OncoQuest Pharmaceuticals or government drug regulatory agencies may review the study data on file.

[0646] Once the subject agrees to participate in the study, they will sign the approved consent form. The original signed consent form will be kept in the subject's permanent file. A copy should be kept by the investigator and another copy should be given to the subject for reference. If study procedures or safety information change and affect the subject's participation, the subject must re-agree to the most current version of the ICF during their participation in the study.

[0647] Financial Disclosure Upon request, Investigators and co-investigators will provide sufficient and accurate financial information to the Sponsor to enable OncoQuest Pharmaceuticals, Inc. or its designee to submit complete and accurate financial certifications or disclosure statements to the appropriate regulatory authorities. Investigators will be responsible for providing information regarding financial interests during the study and for one year after the completion of the study.

[0648] Sponsor Monitoring During the study, OncoQuest Pharmaceuticals, Inc. or its designee will visit the study sites to monitor the progress of the study. These visits will be for the purpose of overseeing adherence to the protocol, completeness of data collection and recording, and accountability for the investigational product.

[0649] By signing this protocol, the Investigator agrees, subject to local regulatory restrictions and institutional and ethical considerations, to allow OncoQuest Pharmaceuticals, Inc. or its designee to inspect and / or copy source documentation (e.g., nuclear medicine reports, clinical laboratory reports, ECGs, x-rays, imaging reports, work logs, and subject medical records) to verify the CRF data.

[0650] It is expected that the investigator and / or other appropriate staff will be available on the day of the visit in case any questions arise.

[0651] Accountability for Study Drugs Both medications will be stored in a secure location and will only be accessible to pharmacists or study staff qualified to dispense and administer the study medication.

[0652] A pharmacist or qualified study staff will maintain an inventory record of both study medications, including details of what was received, the date of dispensing, the subject identification number, and the subject's initials when the medication was administered.

[0653] OncoQuest Pharmaceuticals (or its designee) and the study pharmacist or qualified study staff will conduct a final inventory of study drug supplies at the conclusion or termination of the study. All unused study drug may be disposed of at the site according to site guidelines and an Investigational Drug Supply Destruction Certificate (or similar form) must be completed.

[0654] Destruction of remaining study medication may be delayed until final accountability monitoring.

[0655] Case report forms and original samples Subject data will be recorded on Electronic Data Capture (EDC) Case Report Forms (CRFs). The CRFs will be reviewed for completeness and accuracy by the investigator. The investigator must sign each subject's CRF with a valid electronic signature.

[0656] The Investigator will provide OncoQuest Pharmaceuticals' designated representatives and regulatory authorities with direct access to source documents to verify the data reported in the CRF. Source documents are original documents that can be used by the Investigator or hospital / research institution to verify the existence of subjects and establish the completeness of the data collected during the study.

[0657] Source documents supporting all data recorded on the CRF should be available unless otherwise specified on the CRF, however, data reported on the CRF or transferred from source documents must agree with the source documents or any discrepancies must be explained.

[0658] Protocol Deviations Any deviation from the protocol will be recorded as a protocol deviation.

[0659] OncoQuest Pharmaceuticals and authorized external vendors (if applicable) will follow the guidance in the ICH E3 Structure and Content of Clinical Study Reports with respect to identifying, tracking, classifying and reporting protocol deviations.

[0660] Major protocol deviations are a subset of protocol deviations that may have a significant impact on the completeness, accuracy, and / or reliability of study data or may have a significant impact on the rights, safety, or welfare of study subjects. Major protocol deviations include, but are not limited to:

[0661] - Subjects who participated in the study despite not meeting the inclusion criteria

[0662] -Subjects who met the withdrawal criteria during the study but did not withdraw

[0663] Subjects who received an incorrect treatment or an incorrect dose

[0664] Subjects receiving concomitant therapy were excluded

[0665] Individual subjects who had such protocol deviations will be described in the final clinical trial report by country and center.

[0666] Record-Keeping Important documents (in both written and electronic form) must be retained for not less than 15 years following completion of the clinical trial, unless written authorization for destruction is provided by OncoQuest Pharmaceuticals, Inc. or its designee, or an additional period of retention is required by applicable laws, regulations and / or guidelines.

[0667] Investigators / sites should maintain trial documentation as specified in "Essential Documentation for the Conduct of Clinical Trials" and as required by applicable regulations and / or guidelines. Investigators / sites should take steps to prevent the accidental or premature destruction of these documents.

[0668] Confidentiality of study documentation and patient records Each participating site will maintain appropriate medical and research records related to this study in accordance with section 4.9 of ICH E6 GCP, as well as regulatory and institutional requirements for protecting subject confidentiality.

[0669] By signing this protocol, the Investigator assures OncoQuest Pharmaceuticals that any information provided by OncoQuest Pharmaceuticals will be kept confidential and that such information will be disclosed with appropriate confidentiality understanding with the IRB / IEC committee.

[0670] Data Quality Assurance All subject data pertaining to the study will be recorded on the CRF, unless transmitted electronically to the sponsor or designee (e.g., laboratory data). The investigator is responsible for ensuring that the data is accurate and correct by physically or electronically signing the CRF.

[0671] · Investigators must have accurate documentation (source data) that supports the information provided on the CRF.

[0672] ·Investigators must allow study-related monitoring, audits, IRB / IEC reviews and regulatory inspections, and provide direct access to source data documentation.

[0673] The monitoring strategy (e.g., risk management and mitigation strategies, operational and quality risk-based approaches such as analytical risk-based monitoring), methods, responsibilities and requirements (including response to non-compliance issues, monitoring methodology (central, remote or on-site monitoring)) are described in the monitoring plan.

[0674] OncoQuest Pharmaceuticals, Inc. or its designee, will be responsible for data management for the study, including data quality checks.

[0675] OncoQuest Pharmaceuticals is accountable for actions delegated to it by other individuals (e.g., contract research organizations).

[0676] · Study Monitors will continually verify source data to ensure that data entered into the CRFs by authorized site personnel is accurate, complete, and verifiable from the source documents; that subject safety and rights are protected; and that the study is being conducted in accordance with the currently approved protocol and any other study agreement, ICH GCP, and all applicable regulatory requirements.

[0677] Data Protection All information regarding subject data disclosed to the investigator by the Sponsor or its designee will be kept strictly confidential. Subjects will be assigned a unique identifier by OncoQuest Pharmaceuticals (or a designee). Subject records or data sets transferred to OncoQuest Pharmaceuticals by the third party vendor will contain only the identifier; subject names or any other information that would identify the subject will not be transferred.

[0678] Subjects will be informed that their study-related personal data will be used by the Sponsor in accordance with local data protection laws. The level of disclosure will be explained to subjects.

[0679] Subjects will be informed that their medical records may be inspected by clinical quality assurance auditors or other authorized personnel designated by the sponsor, appropriate IRB / IEC members, and regulatory agency inspectors.

[0680] Facility Exit Criteria Sponsor reserves the right to close any investigational site or terminate the Study at any time for any reason in Sponsor's sole discretion.

[0681] A test facility will be considered closed once all necessary documentation and testing supplies have been collected and a test facility closure visit has been conducted.

[0682] The Investigator may initiate a site closure at any time with reasonable cause and sufficient advance notice.

[0683] Reasons for early closure of a study site by a sponsor or investigator include, but are not limited to, the following:

[0684] The investigator fails to comply with the protocol, IRB / IEC or local health authority requirements, sponsor procedures, or GCP guidelines.

[0685] Improper subject recruitment by investigators

[0686] -Discontinuation of further development of experimental drugs

[0687] Six months after initiation of the protocol, if unforeseen circumstances prevent a particular site from enrolling subjects in the study, the investigator or OncoQuest Pharmaceuticals may request that the site be closed.

[0688] Disclosure Policy The results of this study may not be published or presented at a scientific meeting without the express permission of OncoQuest Pharmaceuticals, Inc. If this is anticipated, the investigator agrees to provide all manuscripts or abstracts to the Sponsor prior to submission, allowing the Sponsor to protect the proprietary information and provide any comments.

[0689] OncoQuest Pharmaceuticals will comply with regulatory requirements for publication of study results. Authorship will be determined by OncoQuest Pharmaceuticals in accordance with the authorship requirements of the International Committee of Medical Journal Editors.

[0690] Please note that routine release of summary results of this study will be permitted and will comply with data privacy guidelines. Subject confidentiality will be maintained by the investigators and OncoQuest Pharmaceuticals in accordance with HIPAA and other regulatory guidelines.

[0691] Appendix A: Timing and Event Schedule [Table 15-1] [Table 15-2]

[0692] [Table 16]

[0693] [References] 1. Aghajanian C, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012; 30(17):2039-45 2. American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018. 3. Battaglia A, Fattorossi A, Madiyalakan MR, Mahnke YD, Nicodemus C. et al. Translational immune correlates of indirect antibody immunization in a randomized phase II study using scheduled combination therapy with carboplatin / paclitaxel plus oregovomab in ovarian cancer patients. Cancer Immunol Immunother. 2020 Mar;69(3):383-397. 4. Berek J, Taylor P, McGuire W, Smith LM, Schultes B, Nicodemus CF. Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer. J Clin Oncol 2009; 27:418-425. 5. Berek JS, Taylor PT, Gordon A, Cunningham MJ, Finkler N, Orr, Jr. J, et al. Randomized, Placebo-Controlled Study of Oregovomab for Consolidation of Clinical Remission in Patients with Advanced Ovarian Cancer. J Clin Oncol 2004; 22:3507-3516. 6. Berek JS, Matulonis,UA, et al: Ann Oncol, Safety and dose modification for patients receiving niraparib. 2018 Aug 1;29(8):1784-1792 7. Braly P, Nicodemus CF, Chu C, et al. The Immune adjuvant properties of front-line carboplatin-paclitaxel: a randomized phase 2 study of alternative schedules of intravenous oregovomab chemoimmunotherapy in advanced ovarian cancer. J Immunother. 2009 Jan; 32(1):54-65 8. Brewer M, Braly P, Madiyalakan M, Bayever E, Nicodemus C, et al. Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: A randomized phase II study. Gynecol Oncol. 2020 Mar;156(3):523-529. 9. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-83. 10. Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615. 11. Coleman RL, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology / Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun; 18(6):779-791 12. De Lorenzo SB, Patel AG, Hurley RM, Kaufmann SH. The Elephant and the Blind Men: Making Sense of PARP Inhibitors in Homologous Recombination Deficient Tumor Cells. Front Oncol. 2013;3:228. 13. Dietrich B, Srinivas S. Urothelial carcinoma: the evolving landscape of immunotherapy for patients with advanced disease. Res Rep Urol. 2018; 10: 7-16. 14. EA Eisenhauer et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). EJC 45 (2009) 228 - 247 15. Fellner C. Ipilimumab prolongs survival in advanced melanoma. Pharm & Ther 2012; 37:503-540. 16. Fendrick JL, Staley KA, Gee MA, McDougald SR, Quirk JG Jr, O’Brien TJ. Characterization of CA125 synthesized by human epithelial amnion WISH cell line. Tumor Biol 1993; 14:310-318. 17. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-13 18. Friedlander et al., A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors. J Clin Oncol 36, 2018 (suppl 5S; abstr 48) 19. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852-861. 20. J. Hamanishi, M. Mandai, T. Ikeda, M. Minami, A. Kawaguchi, T. Murayama, M. Kanai, Y. Mori, S. Matsumoto, S. Chikuma, et al.Safety and antitumor activity of anti-PD-1 antibody, Nivolumab, in patients with platinum-resistant ovarian cancer J. Clin. Oncol., 33 (2015), pp. 4015-4022 21. Jing w, et al., STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models, Journal for ImmunoTherapy of Cancer 2019: Article number:115 22. Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: A Poly(ADP-ribose) Polymerase (PARP) Inhibitor for the Treatment of Tumors with Defective Homologous Recombination. J Med Chem. 2015;58(8):3302-3314. 23. K. Matsuo, Y.G. Lin, L.D. Roman, A.K. Sood. Overcoming platinum resistance in ovarian carcinoma Expert Opin. Investig. Drugs, 19 (2010), pp. 1339-1354 24. Konstantinopoulos PA, Waggoner S, Vidal GA, et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol. 2019 June;1048. 25. Kummar S, Ji J, Morgan R, et al. A Phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012;18(6):1726-173 26. Mirza MR, et al, Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016; 35(22):2154 27. Moore KN, et al., Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):636-648 28. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HH, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373:1803-1813. 29. Msaouel P, Masserelli E. Immune checkpoint therapy in head and neck cancers. Cancer J 2016; 22:108-116. 30. Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-655. 31. Overrman, MJ, McDermott, R, Leach, JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18:1182-1191. 32. Oza AM, Matulonis UA, Malander S, Hudgens S, Sehouli J, Del Campo JM, Mirza MR, et al., Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16 / NOVA): results from a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2018;19(8):1117. 33. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12:252-264. 34. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484-96Jiang X, Pissaloux D, De La Fouchardiere C, et al. The sum of gains and losses of genes encoding the protein tyrosine kinase targets predicts response to multi-kinase inhibitor treatment: Characterization, validation, and prognostic value. Oncotarget 2015;6:26388-99. 35. Pignata S, et al: Randomized Controlled Trial Testing the Efficacy of Platinum-Free Interval Prolongation in Advanced Ovarian Cancer: The MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG Study. J Clin Oncol. 2017;35(29):3347 36. Pilie PG, Gay CM, Byers LA, O'Connor MJ, Yap TA. PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers. Clin Cancer Res. 2019 Jul 1;25(13):3759-3771. 37. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014 Dec 10; 32(35):4025 38. Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348:55-61. 39. Timms KM, Abkevich V, Hughes E, et al. Association of BRCA1 / 2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014;16(6):475. 40. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer. 2004;4(10):814-819. 41. Turner NC, Ashworth A. Biomarkers of PARP inhibitor sensitivity. Breast Cancer Res Treat. 2011;127(1):283-286. 42. Yin BWT, Dnistrian A, Lloyd KO. Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. Int J Cancer 2002; 98:737-740.

[0694] The patent and scientific literature referred to herein demonstrates knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated herein by reference. All published foreign patents and patent applications cited herein are incorporated herein by reference. All other published documents, documents, manuscripts and scientific literature cited herein are incorporated herein by reference.

[0695] Although preferred embodiments have been described and illustrated in the accompanying drawings, it will be apparent to those skilled in the art that modifications may be made without departing from the present disclosure, and such modifications are considered as possible variations within the scope of the present disclosure.

Claims

1. 1. A method of improving the chances of survival for a patient with stage III-IV ovarian cancer, comprising: (a) administering to a patient with stage III-IV ovarian cancer a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) administering to said patient a therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is performed first and step (b) is performed second; Thereby increasing the chances of survival of said patient compared to a control patient diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

2. 2. The method of claim 1, wherein the therapeutically effective amount of niparaliv is about 200 to about 300 mg or 200 mg or 300 mg.

3. The method of claim 2, wherein the therapeutically effective amount of nipararib is administered orally.

4. The method of claims 1-3, wherein said therapeutically effective amount of monoclonal antibody mAb-B43.13 is administered on day 1 of weeks 1, 4, 7, 12, and 20 of said treatment period.

5. The method of any one of claims 1 to 4, wherein the treatment period is 24 weeks.

6. The method of any one of claims 1 to 5, wherein 2 mg of mAb-B43.13 is administered.

7. 7. The method of any one of claims 1 to 6, wherein mAb-B43.13 is administered by infusion over 20 minutes in a volume of 50 mL.

8. 1. A therapeutic agent for use in inhibiting the growth of a stage III-IV ovarian cancer tumor in a patient, comprising: The therapeutic agent comprises mAb-B43.13 (oregovomab) and a parp inhibitor; the parp inhibitor is niraparib; The therapeutic agent may be one of the following: (a) patients with stage III-IV ovarian cancer receiving a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) the patient is administered a therapeutically effective amount of monoclonal antibody mAb-B43.13 according to a schedule comprising administering the therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is a first step and step (b) is a second step; A therapeutic agent thereby increasing the chances of survival of said patient compared to a control patient diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

9. The method of claim 8, wherein the therapeutically effective amount of niparariv is about 200 to about 300 mg or 200 mg or 300 mg.

10. The therapeutic agent of claim 9, wherein the therapeutically effective amount of niparariv is provided by oral administration.

11. The method of claim 8-10, wherein the therapeutically effective amount of monoclonal antibody mAb-B43.13 is administered on days 1 of weeks 1, 4, 7, 12, and 20 of the treatment period.

12. The therapeutic agent according to any one of claims 1 to 11, wherein the period of use is 24 weeks.

13. The method of any one of claims 1 to 12, wherein 2 mg of mAb-B43.13 is used.

14. The method of any one of claims 1 to 13, wherein mAb-B43.13 is administered as a 20 minute infusion in a volume of 50 mL.

15. Said use of a therapeutic agent in inhibiting the growth of stage III-IV ovarian cancer tumors in a patient comprising: The therapeutic agent comprises mAb-B43.13 (oregovomab) and a parp inhibitor; the parp inhibitor is niraparib; The therapeutic agent may be one of the following: (a) patients with stage III-IV ovarian cancer receiving a therapeutically effective amount of niraparib daily for at least 12 weeks; (b) the patient is administered a therapeutically effective amount of monoclonal antibody mAb-B43.13 according to a schedule comprising administering the therapeutically effective amount of monoclonal antibody mAb-B43.13 at weeks 1, 4, 7, 12, and 20 of the treatment period; Step (a) is the first and step (b) is the second Thereby increasing the chances of survival of said patient compared to a control patient diagnosed with stage III-IV ovarian cancer and treated with standard of care chemotherapy.

16. 16. The use of claim 15, wherein the therapeutically effective amount of niparaliv is about 200 to about 300 mg, or 200 mg, or 300 mg.

17. The use according to claim 16, wherein the therapeutically effective amount of nipararib is administered orally.

18. The use of claims 15 to 17, wherein said therapeutically effective amount of monoclonal antibody mAb-B43.13 is used on days 1 of weeks 1, 4, 7, 12 and 20 of said treatment period.

19. The use according to any one of claims 15 to 18, wherein the period of use is 24 weeks.

20. The use according to any one of claims 15 to 19, wherein 2 mg of mAb-B43.13 is used.

21. The use according to any one of claims 15 to 20, wherein mAb-B43.13 is administered as an infusion over 20 minutes in a volume of 50 mL.

Images