Key Inclusion Criteria:

• Participants must have histologically or cytologically confirmed high grade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
• Participants may be enrolled regardless of FR? expression level.
• Participants must have received 1 to 4 prior lines of therapy.

• Participants must have received prior treatment with the following therapies:

  • Platinum chemotherapy
  • Prior bevacizumab treatment is required, if labeled and available as standard of care per institutional guidelines, unless the participant has a documented contraindication or due to precautions/intolerance
  • Participants with known or suspected deleterious germline or somatic breast cancer gene (BRCA) mutations and who achieved a complete or partial response to platinum-based chemotherapy must have been treated with a poly ADP-ribose polymerase (PARP) inhibitor as maintenance treatment unless the participant is not eligible for treatment with PARP inhibitor

  • Mirvetuximab soravtansine, if:

    • Mirvetuximab soravtansine is available in the enrollment region, and
    • The participant is eligible based on positive FR? expression per Food and Drug Administration (FDA)-approved (or local equivalent) test, and
    • The participant does not have a documented medical exception, including chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision.

• Participants must have platinum-resistant disease:

  • Participants who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum therapy, and must have either had a response (CR or PR) or had non-measurable disease at the start of platinum-based therapy, and then progressed between > 91 days and ? 183 days after the date of the last dose of platinum.
  • Participants who have received 2 to 4 lines of platinum-based therapy must have progressed on or within 183 days after the date of the last dose of platinum.

Key Exclusion Criteria:

• Prior therapy with an antibody-drug conjugate containing a topoisomerase 1 inhibitor.
• Have primary platinum-refractory disease, defined as ovarian cancer that did not respond (CR or PR) to or progressed ? 91 days after the last dose of a first-line platinum-containing regimen.
• History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ?90%), including, but not limited to, adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ, or Stage I uterine cancer.
• Known active central nervous system metastases or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids and anticonvulsants prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. Participants with suspected brain metastases at screening should undergo a computed tomography (CT)/magnetic resonance imaging (MRI) of the brain prior to study entry.
• Hospitalization or clinical symptoms due to gastrointestinal obstruction within the past 91 days or radiographic evidence of gastrointestinal obstruction at the time of screening. Enrollment of participants who currently require parenteral nutrition must be discussed with the study medical monitor to determine eligibility.
• Ascites requiring frequent paracentesis (more often than approximately every 4 weeks) for symptomatic management. Enrollment of participants with an indwelling peritoneal catheter must be discussed with the medical monitor to determine eligibility.

NOTE: Other protocol-defined Inclusion/Exclusion criteria may apply.

**This study is open to SJMH (Ann Arbor site 84029), and Sparrow (site 84049) only.

6.1 Inclusion Criteria
Subjects are eligible to be included in the study only if all of the following criteria apply:
1. Adults 18 years old or older.
2. Subjects with newly diagnosed epithelial adenocarcinoma of ovarian, fallopian tube or peritoneal origin FIGO Stage III or IV disease.
3. Eligible histologic epithelial cell types: high grade serous adenocarcinoma, high grade endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma not otherwise specified (N.O.S.).
4. Completed debulking surgery (either primary debulking surgery or interval debulking surgery at the discretion of the investigator), as defined below:
a. For subjects who undergo primary debulking surgery (Cohort 1 - Primary Surgery):
i. Cycle 1 of chemotherapy ± oregovomab/placebo must be anticipated to occur within 6 weeks after primary debulking surgery, and
ii. The primary debulking surgery is optimal, R1 or R0 (defined as R1, macroscopic no greater than 1 cm in diameter, or R0, microscopic or no evidence of tumor).
b. For subjects who will undergo interval debulking surgery (Cohort 2 ? NACT/Interval Surgery):
i. Subject must have received neoadjuvant treatment with 3 cycles of paclitaxel 175 mg/m2 IV over 3 hours every approximately 3 weeks (21 Days), followed by carboplatin area under the curve (AUC) 5-6
administered intravenously (IV) approximately every 3 weeks (21 Days), and
ii. Cycle 4 of chemotherapy ± oregovomab/placebo must be anticipated to occur within 6 weeks after interval debulking surgery, and
iii. The interval debulking surgery is optimal, R1 or R0 (defined as R1, macroscopic no greater than 1 cm in diameter, or R0, microscopic or no evidence of tumor).
5. Suitable venous access for the study-required procedures.
6. Cohort 1 ? Primary Surgery: Preoperative serum CA-125 levels = 50 U/mL, or in Cohort 2 ? NACT + Interval Surgery: serum CA-125 levels = 50 U/mL prior to first pre-operative chemotherapy.
7. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) = 1,500/µL
b. Platelets = 100,000/µL

c. Hemoglobin = 8.0 g/dL (Note: Blood transfusion is permitted up to 48 hours before first dose of study treatment).
8. Adequate liver function:
a. Bilirubin < 1.5 times upper limit normal (ULN)
b. Lactate Dehydrogenase (LDH), SGOT/AST and SGPT/ALT < 2.5 times ULN
c. Albumin >3.5 g/dL
9. Adequate renal function:
a. Creatinine = 1.5 times ULN
10. ECOG Performance Status of 0 or 1.
11. For women of childbearing potential, must be willing to avoid pregnancy by using a highly effective method of contraception from the first dose of study treatment to 60 days after last dose of study treatment. Adequate contraception is defined in Section 8.2.5.
12. Sign informed consent and authorization permitting release of personal health information.
13. Willingness and ability to complete patient quality of life questionnaires.

6.2 Exclusion Criteria
Subjects are excluded from the study if any of the following criteria apply:
1. BRCA1 or BRCA2 germline gene mutation test result with:
a. Positive, ambiguous or inconclusive result available within 28 days prior to starting study treatment, or
b. Known BRCA1 and BRCA2 somatic mutations, and known positive germline, or
c. Somatic Homologous Recombination Deficiency (HRD) who will receive PARP inhibitor front-line maintenance therapy.
2. Subjects with mucinous adenocarcinoma and low-grade adenocarcinoma.
3. Female subjects who are lactating and breastfeeding, or have a positive serum pregnancy test within 7 days prior to the first dose of study treatment (C1D1 for Cohort 1 or C4D1 for Cohort 2).
4. Any serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the completion of treatment according to this protocol.
5. Active autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), or ankylosing spondylitis requiring active disease modifying treatment.
6. Known allergy to murine proteins or hypersensitivity to any of the excipients of the oregovomab, paclitaxel, or carboplatin.
7. Chronically treated with immunosuppressive drugs such as cyclosporine, adrenocorticotropic hormone (ACTH), etc. (see Appendix G).
8. Chronic therapeutic corticosteroid use, defined as > 5 days of prednisone or equivalent, with the exception of inhalers or those on a pre-planned steroid taper. (Note: Premedication with corticosteroids per institutional standard of care is allowed.)

9. Recognized acquired, hereditary, or congenital immunodeficiency disease, including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia.
10. Clinically significant active infection(s) at the time of screening.
11. Any of the following conditions (on-study testing is not required):
a. Known HIV-infected subjects unless on effective anti-retroviral therapy with an undetectable viral load within 6 months, or
b. Known or suspected hepatitis B if active infection (patients with chronic hepatitis B infection must have an undetectable HBV viral load on suppressive therapy, if indicated; positive surface antibody alone is not an exclusion), or
c. Known or suspected hepatitis C infection which has not been treated and cured unless currently on treatment with an undetectable viral load).
12. Uncontrolled or life-threatening diseases compromising safety evaluation.
13. Diagnosed or treated for another malignancy within 5 years before the first dose, or previously diagnosed with another malignancy and have any evidence of residual disease. Subjects with non-melanoma skin cancer or cervix carcinoma in situ are not excluded if they have undergone complete resection. Synchronous endometrial cancer, but a prior diagnosis of endometrial cancer within 5 years is not excluded if all of the following conditions are met: Stage IA, superficial myometrial invasion, without lymphovascular invasion, grade 3 or not poorly differentiated subtypes including papillary serous, clear cell or other FIGO Grade 3 lesions.
14. Contraindications to the use of pressor agents.
15. Undergone more than one surgical debulking or have not recovered from surgery.
16. Anticipated treatment with any other anti-cancer medications, including bevacizumab, poly (ADP-ribose) polymerase (PARP) inhibitors, or any investigational agent(s) during the study.
17. History or evidence upon physical examination of CNS disease, seizures not controlled with standard medical therapy, or any brain metastases.
18. Any of the following cardiovascular conditions:
a. Acute myocardial infarction within 6 months before the first dose of study treatment.
b. Current history of New York Heart Association (NYHA) Class III or IV heart failure (see Appendix H).
c. Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic clinically significant findings.
19. Unable to read or understand or unable to sign the necessary written consent before starting treatment

-Patients must be candidates for cytoreductive surgery and consent to have their surgical treatment determined by randomization
-Patients must have histologic diagnosis of epithelial ovarian carcinoma, peritoneal primary or fallopian tube carcinoma, which is now recurrent.
-Patients with the following histologic epithelial cell types are eligible: Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma NOS
-Patients must have had a complete response to front-line platinum-taxane therapy (at least three cycles)
-Patients must have a treatment-free interval without clinical evidence of progressive disease lasting at least 6 months.
-Patients must have clinically evident recurrent disease. 
-GOG PS must be 0-2
-Patients must not have received mor than one previous regimen of chemotherapy
-Patients must not be receiving concurrent immunotherapy or radiotherapy
-Patients who have received prior RT to any portion of the abdominal cavity or pelvis are excluded.
-Patients who have already undergone secondary cytoreduction for recurrence are excluded
-Patients who have received prior chemotherapy for any abdominal or pelvic tumor (other than gyn) are excluded

-Patients initially diagnosed with low-grade serous ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas OR
-Patients initially diagnosed with serous borderline ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas
-Patients must have documented low-grade serous carcinoma; confirmation must occur by prospective pathology review prior to study entry; the prospective pathology review must be done on tissue from the recurrent carcinoma
-At least 4 weeks must have elapsed since any major surgery
-All patients must have measurable disease
-Patients must have recurred or progressed following at least one platinum-based chemotherapy regimen
-Patients may have received an unlimited number of prior therapy regimens
-Patients may not have received all of the five choices in the "standard therapy" arm
-Patients must have a GOG performance status of 0 or 1
-If letrozole is selected as the control therapy, patients must be postmenopausal
-No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
-If patients have had a potential index lesion radiated, it must have progressed post radiation therapy to be used as a measurable eligibility lesion
-Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor therapy
-Patients with known leptomeningeal or brain metastases or spinal cord compression should be excluded from this clinical trial

-Patients must have pathologically proven non-small cell lung cancer (all histologic types) confirmed by tumor biopsy and/or fine-needle aspiration. Disease must be Stage IV as defined in Section 4.0 , or recurrent. The primary diagnosis of non-small cell lung cancer should be established using the current WHO/IASLC-classification of Thoracic Malignancies.
-Patients must either be eligible to be screened at progression on prior treatment or to be pre-screened prior to progression on current treatment.
-Screening at progression on prior treatment:

--To be eligible for screening at progression, patients must have received at least one line of systemic therapy for any stage of disease (Stages I-IV) and must have progressed during or following their most recent line of therapy.

-Pre-Screening prior to progression on current treatment:

--To be eligible for pre-screening, current treatment must be for Stage IV or recurrent disease and patient must have received at least one dose of the current regimen. Patients must have previously received or currently be receiving a platinum-based chemotherapy regimen or anti-PD-1/PD-L1 therapy, alone or in combination (e.g. Nivolumab or Pembrolizumab). Patients on first-line treatment are eligible upon receiving Cycle 1, Day 1 infusion.

Note: Patients will not receive their sub-study assignment until they progress and the LungMAP Notice of Progression is submitted.
-Patients must have adequate tumor tissue available, defined as ? 20% tumor cells and ? 0.2 mm3 tumor volume.

• The local interpreting pathologist must review the specimen.

• The pathologist must sign the LungMAP

Local Pathology Review Form confirming tissue adequacy prior to Step 1 registration.
-Patients must agree to have this tissue submitted to Foundation Medicine for common broad platform CLIA biomarker profiling, PD-L1, and c-MET IHC (see Section 15.2). If archival tumor material is exhausted, then a new fresh tumor biopsy that is formalin-fixed and paraffin-embedded (FFPE) must be obtained. Patients who need the fresh biopsy must also submit whole peripheral blood for ctDNA testing. A tumor block or FFPE slides 4-5 microns thick must be submitted. Bone biopsies are not allowed. If FFPE slides are to be submitted, at least 12 unstained slides plus an H&E stained slide, or 13 unstained slides must be submitted. However, it is strongly recommended that 20 FFPE slides be submitted. Note: Previous next-generation DNA sequencing (NGS) will be repeated if done outside this study for sub-study assignment.
-Patients must agree to have any tissue that remains after testing retained for the use of sub-study Translational Medicine (TM) studies at the time of consent the patient is enrolled in.
-Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have progressed following all standard of care targeted therapy. EGFR/ALK/ROS/BRAF testing is not required prior to Step 1 registration, as it is included in the Foundation One testing for screening/pre-screening.
-Patients must have Zubrod performance status 0-1 (see Section 10.2) documented within 28 days prior to Step 1 registration.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health IHA (Ann Arbor, Brighton, Canton, Chelsea), Livonia, Genesys

Eligibility Criteria:

 3.3.1 Documentation of Disease

Patients must have a morphologically-confirmed diagnosis of MDS with an IPSS-R score ≥4 (See Appendix VI for IPSS-R scoring) [2]. Patients must have a detectable pathogenic IDH2 mutation based on the NCI Myeloid Panel. 

3.3.2 Prior Treatment 

-No prior treatment with DNA methyltransferase inhibitors (ASTX727, azacitidine, or decitabine). 

-Prior treatment with growth factors (ESA, g-CSF, TPO agonist), lenalidomide or luspatercept is allowed with a maximum limit of 1 month of exposure.

-Patients with therapy-related MDS are allowed.

3.3.3 Age ≥ 18 years

3.3.4 ECOG Performance Status ≤ 2

3.3.5 Required Initial Laboratory Values

-Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)*

-AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)

-GFR ≥ 30 mL/min/1.73m2**  

 *Unless elevated due to Gilbert’s syndrome. In patients with Gilbert’s syndrome, if the total bilirubin is ≤ 3.0 × ULN, then they are eligible for enrollment.

**To be calculated using Cockroft Gault formula.

3.3.6 Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done as part of screening lab work prior to registration is required.

3.3.7 Comorbid Conditions

-Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

-HIV: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.

-Hepatitis B: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

-Hepatitis C: Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load 

**PLEASE SEE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**