• Age ≥ 16 years.
• Advanced unresectable or metastatic sarcoma.

Cohort 1

• Leiomyosarcoma (LMS)/Liposarcoma (LPS).

Cohort 2

• Other sarcoma histologies (excluding gastrointestinal stromal tumors).
• Received at least 1 prior standard chemotherapy. For cohort 1 patients, this must have included a prior anthracycline.
• Measurable disease by RECIST 1.1.
• Adequate hematologic, renal, hepatic function.
• Adequate creatine phosphokinase.
• ECOG performance status ≤ 1.
• Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal (LLN).
• Women of childbearing potential and men must agree to use adequate contraception from signing informed consent to at least 6 months (females) and 5 months (men) after study drug treatment.
• Men must agree to use barrier contraception or abstinence and not donate sperm during treatment and for 5 months after the last dose of study treatment. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.
• Left ventricular ejection fraction ≥ institutional LLN.
• Ability to understand and the willingness to sign a written informed consent.
• Must have a life expectancy ≥ 16 weeks.

• Prior therapy with PARP inhibitor, including olaparib.
• Prior therapy with trabectedin.
• Additional active malignancy or treatment for alternative cancer (excluding non-melanoma skin cancer) requiring treatment within the past two years.
• Pregnant or breastfeeding women.
• Known hypersensitivity to trabectedin or olaparib.
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
• Patients with myelodysplastic syndrome (MDS) /acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Immunocompromised patients; e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• Patients with known active hepatitis (i.e., Hepatitis B or C).
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks.
• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St. John’s Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• Participation in another clinical study with an investigational product administered in the last 30 days prior to anticipated study treatment.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Has received a live vaccination with 2 weeks of enrollment.
• Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.
• Involvement in the planning and/or conduct of the study.
• Previous enrollment in the present study.

• Patients with a pituitary/sellar lesion undergoing endoscopic endonasal resection.

• Patients undergoing open non-endoscopic approaches to their pituitary/sellar lesion.

• Adult patients, ≥ 18 years of age.
• Willing and able to complete informed consent for harvesting tissue for research.

• Patients < 18 years of age.

For Groups 1-4

• Patients seeking clinical treatment for non-specific LBP through sports medicine, PM&R, or orthopedic physical therapy (PT) or through chiropractic care at Mayo Clinic.
• Subjects between 18-65 years old.

For Group 5

• Subjects between 18-65 years old.
• Self-reported non-specific LBP from the Tonal customer base.
• Specific to Group 5 subjects, participants recruited from the Tonal customer base will be matched (as near as possible) to existing clinical subjects recruited for Groups 1-4.

• Acute and traumatic LBP onset (identifiable by singular event such as a car accident). Specific to Group 5, Tonal customers will be excluded if they indicate that they are seeking external physical therapy or chiropractic care to treat their LBP.
• Pregnant females. Pregnancy will be verbally assessed in female participants.  In Groups 1-4, this will be addressed during consent. In Group 5 this will be addressed during the question screening.  Female subjects will be asked to inform the study team if they become pregnant during the study period. If a subject becomes pregnant, they will be excluded from participation in any future study activities as pregnancy is a known confounding factor to lower back pain.

For Groups 1-4

• Patients seeking clinical treatment for non-specific LBP through sports medicine, PM&R, or orthopedic physical therapy (PT) or through chiropractic care at Mayo Clinic.
• Subjects between 18-65 years old.

For Group 5

• Subjects between 18-65 years old.
• Self-reported non-specific LBP from the Tonal customer base.
• Specific to Group 5 subjects, participants recruited from the Tonal customer base will be matched (as near as possible) to existing clinical subjects recruited for Groups 1-4.

• Acute and traumatic LBP onset (identifiable by singular event such as a car accident). Specific to Group 5, Tonal customers will be excluded if they indicate that they are seeking external physical therapy or chiropractic care to treat their LBP.
• Pregnant females. Pregnancy will be verbally assessed in female participants.  In Groups 1-4, this will be addressed during consent. In Group 5 this will be addressed during the question screening.  Female subjects will be asked to inform the study team if they become pregnant during the study period. If a subject becomes pregnant, they will be excluded from participation in any future study activities as pregnancy is a known confounding factor to lower back pain.

• Adult patients ≥ 18 years old.
• COVID-19+ and COVID-19- individuals (controls), as determined by qPCR.

• Individuals < 18 years of age.
• Pregnant women.
• Individuals with ambiguous COVID-19 result by qPCR.
• Individuals who have received one, or both doses of the Covid 19 vaccine.
• Individuals who are recieving a monoclonal antibody infusion.

• 18 years of age or older.
• Biologically female.
• Non-Hispanic Black (NHB).
• Diagnosis of breast and/or ovarian cancer or family history of breast and ovarian cancer.

• Under age of 18.
• Not biologically female.
• Ethnicity other than NHB.
• Has not been diagnosed with breast and/or ovarian cancer and does not have a family history breast and ovarian cancer.

Patients must meet all of the following criteria to be considered for inclusion in this clinical investigation:

• 21 years of age or older.
• Presence of severe degenerative mitral regurgitation with mid-segment posterior leaflet prolapse (without commissural involvement) by echocardiographic study.
• Mitral leaflet coaptation surface sufficient to reduce mitral regurgitation without undue leaflet tension, based on the judgment of the Echocardiographic Core Lab.
• Competent to sign informed consent and able to return for follow-up and is capable of participating in all testing associated with this clinical investigation.

Patients will be excluded if any of the following criteria apply:

• Functional mitral regurgitation (FMR).
• Evidence of anterior or bileaflet prolapse.
• Severe mitral annular calcification (MAC).
• Moderate or greater leaflet calcification.
• Fragile or thinning apex (e.g., LV aneurysm).
• Have undergone cardiac or peripheral vascular procedures within 30 days prior to the trial procedure.
• Planned cardiac or peripheral vascular procedures within 30 days after the trial procedure.
• Requirement for concomitant cardiac surgery.
• Severe pulmonary hypertension (pulmonary artery systolic pressure > 60mmHg).
• Severe aortic stenosis or insufficiency.
• Severe tricuspid regurgitation. (Patients with mild or moderate tricuspid regurgitation are not excluded.)
• Left or right ventricular ejection fraction (LVEF or RVEF) < 30% as measured by the core lab.
• Any history of endocarditis.
• Contraindication to cardiac surgery, including hostile chest or history of mediastinal radiation.
• Previous structural heart intervention (e.g., any heart valve replacement or repair procedures) with the exceptions of coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
• Stroke within 30 days prior to index procedure.
• ST segment elevation myocardial infarction (STEMI) requiring intervention within 30 days prior to index procedure.
• Evidence of cirrhosis or hepatic synthetic failure (Child-Pugh Class B or higher, [or MELD score of ≥ 13]).
• Renal insufficiency CKD Stage 3b or worse (GFR < 45 ml/min/1.73 m^2).
• Hemodynamic instability or cardiogenic shock at the time of enrollment (e.g., requiring inotropic support or mechanical support devices).
• History of bleeding diathesis or coagulopathy or leukopenia (WBC < 3000 mcL) or acute anemia (Hb < 9 g/dL) or thrombocytopenia (platelets < 50,000 cells mcL).
• Refuse blood products.
• Planned treatment with any other investigational device or procedure through 1-year follow-up, or who are currently participating in an investigational drug or device trial.
• Carotid stenosis ≥ to 80% at time of enrollment.
• Rheumatic heart disease including rheumatic mitral stenosis.
• Pregnant or lactating at the time of enrollment (women of childbearing age should have negative pregnancy test within 72 hours of surgery) or planning pregnancy within the next 12 months.
• Concurrent medical condition with a life expectancy of less than 12 months in the judgment of the Investigator.
• Condition or conditions that, in the opinion of the Investigator, precludes participation, including willingness to comply with all follow-up procedures.
• Contraindication for transesophageal echocardiography (TEE), including esophageal spasm, esophageal stricture, esophageal laceration, esophageal perforation, esophageal diverticula (e.g., Zenker's diverticulum).
• Echocardiographic evidence of intracardiac mass (e.g., left ventricular, atrial, or appendage thrombus, myxoma, or vegetation).
• Cannot tolerate procedural anticoagulation or post-procedure antiplatelet regimen.

Intra-operative

• No longer meets eligibility criteria based on intra-operative assessment.

Eligibility last updated 4/25/22. Questions regarding updates should be directed to the study team contact.

• Pre- or postmenopausal. Postmenopausal women are defined as:
  • ≥ 60 years of age with no vaginal bleeding over the prior year; or
  • < 60 years with "premature menopause" or "premature ovarian failure" manifest itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards; or
  • Surgical menopause with bilateral oophorectomy.
    • Note: Premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy.
• If possible, a biopsy of metastatic breast cancer tissue should be obtained to provide histological or cytological confirmation of ER+/HER2− disease as assessed by a local laboratory, according to American Society of Clinical Oncology/College of American Pathologists guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject is ER+ and HER2−.
• Locally advanced and/or metastatic breast cancer with radiological or clinical evidence of progression on the first or 2nd lines of hormonal therapy for metastatic disease. Progression may have occurred on no more than 2 of the following endocrine treatments for metastatic breast cancer: an aromatase inhibitor (AI) and/or fulvestrant either as monotherapy or in combination with any commercially approved CDKi; and/or the combination of fulvestrant and alpelisib; and/or tamoxifen; and/or the combination of exemestane/everolimus.
  • Note: before starting study treatment, subjects should have stopped any CDKi for at least 21 days.
• Subjects must have had no evidence of progression for at least 6 months during their first hormonal treatment for advanced breast cancer.
• At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N.
  • Note: the Sponsor's blood ctDNA assay must be used but tissue sequencing (if done) may be done by a validated commercial laboratory.
  • Note: A positive ESR1 mutation in tissue or ctDNA using a validated commercial assay if done prior or at the time of disease progression is acceptable to meet this entry criteria. However, blood for ctDNA must still be obtained for genomic analyses using the sponsor's ctDNA assay.
• Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.
• Subjects may have received one cytotoxic chemotherapy regimen for metastatic disease as well as those who received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial can be enrolled but must be free of all chemotherapy acute toxicity excluding alopecia and Grade 2 peripheral neuropathy before study entry. A washout period of at least 21 days is required between last chemotherapy dose and entry into the study.
• Stable breast cancer metastasis to the brain is allowed as long as the subject has received radiotherapy and not demonstrated any evidence of brain metastasis progression for at least 3 months after the completion of radiotherapy.
• ECOG performance score of 0 or 1.
• Adequate organ function as shown by:
  • absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3;
  • platelet count ≥ 100,000 cells/mm^3;
  • hemoglobin ≥ 8.0 g/dl;
  • ALT and AST levels ≤ 3 upper limit of normal (ULN) or ≤ 5 in the presence of liver metastasis;
  • Total serum bilirubin ≤ 1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert Syndrome);
  • Alkaline phosphatase level ≤ 3 ULN;
  • Creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula;
  • International normalized ratio (INR) and activated partial thromboplastin (aPTT) < 2.0 X ULN.
• Able to swallow tablets.
• Able to understand and voluntarily sign a written informed consent before any screening procedures.

• Lymphangitic carcinomatosis involving the lung.
• Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
• Radiotherapy within 30 days prior to entry into the study except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to entry into the study. Subjects must have recovered from radiotherapy toxicities prior to entry into the study.
• Subjects with known inactivating RB1 mutations or deletions (Screening for RB1 mutation is not required for entry).
• History of long QTC syndrome or a QTC of > 480 msec.
• History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6 months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment and there is no evidence for active thrombosis. The use of low-dose ASA is permitted.
• Subjects on concomitant strong CYP3A4 inhibitors such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir. 
• Subjects on strong and moderate CYP3A4 inducers such as amprenavir, barbiturates, carbamazepine, clotrimazole, dexamethasone, efavirenz, ethosuximide, griseofulvin, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, chronic prednisone treatment, primidone, rifabutin, rifampin, rifapentine, ritonavir, topiramate.
• Any significant co-morbidity that would impact the study or the subject's safety. Since CDKi have reported the occurrence of interstitial lung disease (ILD), subjects with a history of ILD and those with severe dyspnea at rest or requiring oxygen therapy should not enter the study.
• Subject has an active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics at the time of initiating study treatment).
• History of a positive human immunodeficiency virus (HIV) or hepatitis B virus (HBV) test. Screening is not required for enrollment.
• Subjects with hepatitis C virus (HCV) at Screening who still have a viral load. Subjects previously treated and achieved a HCV cure (no viral load) can be entered into the study.
• History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery, or early-stage cervical cancer.
• Positive pregnancy test (only if premenopausal).
• History of non-compliance to medical regimens.
• Unwilling or unable to comply with the protocol.
• Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

• Participants with relapsed or refractory diffuse and transformed large B-cell lymphoma (R/R DLBCL). DLBCL and cell of origin (GCB versus non-GCB) will be histologically determined by local pathology assessment for the purposes of study eligibility and stratification.
• Participants must have R/R disease following 2 or more lines of prior systemic therapy.
• Participants must be HSCT or CAR-T ineligible according to the investigator and must meet at least one of the following criteria:
  • One or more co-morbidities, including cardiac, pulmonary, renal or hepatic dysfunction that in the opinion of the Investigator make the subject medically unfit to received HSCT or CAR-T therapy;
  • Active disease following induction and salvage chemotherapy;
  • Inadequate stem cell mobilization (for HSCT);
  • Relapse following prior HSCT or CAR-T;
  • Unable to receive CAR-T therapy due to financial, geographic, or insurance issues.
• Participants will need to have a formalin-fixed paraffin-embedded tumor tissue (obtained ≤ 4 weeks before Day 1) submitted to the central pathology lab.
• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2.
• Participants must have fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and bidimensional measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist within 28 days of Day 1.
• Participants must be registered into the mandatory lenalidomide REMS® program and be willing to comply with its requirements. Per standard lenalidomide REMS® program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the lenalidomide REMS® program.

• History of another malignancy within 2 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy.
• History of progressive multifocal leukoencephalopathy (PML).
• Active cerebral/meningeal disease related to the underlying malignancy. Subjects with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior CNS disease has been effectively treated and without progression for at least 3 months.
• Any uncontrolled Grade 3 or higher (per NCI CTCAE version 5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted.
• Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed 3 weeks prior to first dose of study drug, unless underlying disease has progressed on treatment
• Participants who are breastfeeding.
• Known hypersensitivity to any study drug or excipient contained in the drug formulation of the study drugs.
• Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection (positive by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the last 6 months). Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
• Participants with previous allogeneic HSCT if they meet either of the following criteria:
  • < 100 days from HSCT;
  • Active acute or chronic graft-versus-host disease (GVHD) or receiving immunosuppressive therapy as treatment for or prophylaxis against GVHD.
• Previous treatment with brentuximab vedotin or lenalidomide.
• Current therapy with immunosuppressive medications (including steroids), other systemic anti-neoplastic, or investigational agents:
  • Prednisone (or equivalent) ≤ 10 mg/day may be used for non-lymphomatous purposes.
• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to the first dose of study drugs.
• Congestive heart failure, Class III or IV, by the NYHA criteria.
• Grade 2 or higher peripheral sensory or motor neuropathy at baseline.

• Written informed consent.
• Subjects who successfully completed all of the treatment period and the follow-up  period in any of the following studies:
  • CQGE031C2302, CQGE031C2303, CQGE031C2202 or  CQGE031C1301.
• Male and female, ages ≥ 18 years of age.
• Willing and able to complete a daily symptom eDiary for the duration of the study and  adhere to the study visit schedule.

• Use of investigational drugs, other than those in use in the preceding studies, at the  time of enrollment.
• Use of omalizumab within 16 weeks of Screening.
• History of hypersensitivity to the study drug ligelizumab or its components, or to  drugs of similar chemical classes.
• New onset or signs and symptoms of any form of chronic urticarias other than CSU  during the preceding studies CQGE031C2302, CQGE031C2303 or CQGE031C2202.  
• Diseases with possible symptoms of urticaria or angioedema.
• Subjects with evidence of helminthic parasitic infection.
• Documented history of anaphylaxis.
• Pregnant or nursing (lactating) women.

Step 0 Eligibility Criteria

• No age restriction.
• Patient must have a prior or current cancer diagnosis (e.g., solid tumor or hematologic malignancy) that fits into any one of the following categories:
  • Patient is receiving active treatment (defined as current treatment or treatment within the past 6 weeks) or will begin receiving treatment within the next 2 weeks for any CNS or hematologic malignancy or metastatic (Stage IV) solid tumor. Eligible treatment types for hematologic malignancy or metastatic cancer are chemotherapy, immunotherapy, monoclonal antibody therapy (e.g., rituximab, trastuzumab, cetuximab), targeted therapy (e.g., BRAF/MEK inhibitor, EGF-R inhibitor), endocrine therapy, radiation therapy, or targeted radionuclide therapy; or
  • Patient is receiving treatment (defined as current treatment or treatment within the past 6 weeks) or will begin receiving treatment within the next 2 weeks for non-metastatic (Stage I-III) solid tumor. Eligible treatment types for nonmetastatic cancer patients are intravenous chemotherapy, immunotherapy, targeted therapy, radiation therapy, targeted radionuclide therapy, or monoclonal antibody therapy, except trastuzumab/pertuzumab if not accompanied by chemotherapy; or
  • Patient has received an allogenic stem cell transplant or CAR-T cell or other modified cellular therapy at any time; or
  • Patient is currently receiving treatment or prophylaxis for Graft vs. Host Disease.

Testing for SARS CoV-2

• Patient must have a pending or known positive viral test result for SARS-CoV-2:
  • Patients with prior negative viral SARS-CoV-2 test(s) are eligible if they are being tested again;
  • Patients 18 years of age and older with prior positive viral SARS-CoV-2 test(s) more than 14 days prior to enrollment to Step 1 are not eligible.
  • Patient must be undergoing or have undergone testing for SARS CoV-2:
• HIV-infected patients are eligible.
• Patients with CNS metastases are eligible.
• Co-enrollment on other clinical trials (for cancer or for COVID-19) is allowed.

Step 1 Eligibility Criteria

• Patient must have a documented positive viral SARS-CoV-2 test:
  • For patients 18 years of age or older, the specimen collection for the positive test must have occurred no earlier than 14 days prior to enrollment to Step 1;
  • For patients under 18 years of age, the specimen collection for the positive test must have occurred after January 31, 2020.
  • The viral test can be either a nucleic acid (PCR) test or an antigen test. Serological or antibody tests are not allowed.
  • The test must have received Emergency Use Approval (EUA) from the FDA and be performed in a CLIA certified lab or patient care setting operating under a CLIA Certificate of Waiver. A full list of tests that have been approved under the EUA can be accessed at:

https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19- emergency-use-authorizations-medical-devices/vitro-diagnostics-euas.

• Any specimen source (e.g., nasopharyngeal swab, oropharyngeal swab, etc.) is allowable for the viral SARS-CoV-2 test.

Step 0 Eligibility Criteria

• No age restriction.
• Patient must have a prior or current cancer diagnosis (e.g., solid tumor or hematologic malignancy) that fits into any one of the following categories:
  • Patient is receiving active treatment (defined as current treatment or treatment within the past 6 weeks) or will begin receiving treatment within the next 2 weeks for any CNS or hematologic malignancy or metastatic (Stage IV) solid tumor. Eligible treatment types for hematologic malignancy or metastatic cancer are chemotherapy, immunotherapy, monoclonal antibody therapy (e.g., rituximab, trastuzumab, cetuximab), targeted therapy (e.g., BRAF/MEK inhibitor, EGF-R inhibitor), endocrine therapy, radiation therapy, or targeted radionuclide therapy; or
  • Patient is receiving treatment (defined as current treatment or treatment within the past 6 weeks) or will begin receiving treatment within the next 2 weeks for non-metastatic (Stage I-III) solid tumor. Eligible treatment types for nonmetastatic cancer patients are intravenous chemotherapy, immunotherapy, targeted therapy, radiation therapy, targeted radionuclide therapy, or monoclonal antibody therapy, except trastuzumab/pertuzumab if not accompanied by chemotherapy; or
  • Patient has received an allogenic stem cell transplant or CAR-T cell or other modified cellular therapy at any time; or
  • Patient is currently receiving treatment or prophylaxis for Graft vs. Host Disease.

Testing for SARS CoV-2

• Patient must have a pending or known positive viral test result for SARS-CoV-2:
  • Patients with prior negative viral SARS-CoV-2 test(s) are eligible if they are being tested again;
  • Patients 18 years of age and older with prior positive viral SARS-CoV-2 test(s) more than 14 days prior to enrollment to Step 1 are not eligible.
  • Patient must be undergoing or have undergone testing for SARS CoV-2:
• HIV-infected patients are eligible.
• Patients with CNS metastases are eligible.
• Co-enrollment on other clinical trials (for cancer or for COVID-19) is allowed.

Step 1 Eligibility Criteria

• Patient must have a documented positive viral SARS-CoV-2 test:
  • For patients 18 years of age or older, the specimen collection for the positive test must have occurred no earlier than 14 days prior to enrollment to Step 1;
  • For patients under 18 years of age, the specimen collection for the positive test must have occurred after January 31, 2020.
  • The viral test can be either a nucleic acid (PCR) test or an antigen test. Serological or antibody tests are not allowed.
  • The test must have received Emergency Use Approval (EUA) from the FDA and be performed in a CLIA certified lab or patient care setting operating under a CLIA Certificate of Waiver. A full list of tests that have been approved under the EUA can be accessed at:

https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19- emergency-use-authorizations-medical-devices/vitro-diagnostics-euas.

• Any specimen source (e.g., nasopharyngeal swab, oropharyngeal swab, etc.) is allowable for the viral SARS-CoV-2 test.

• Subject must provide written informed consent prior to any clinical investigation related procedure.
• Subject is at least 18 years (or the minimum age required by local law to consent for participation in a clinical investigation) or older at the time of enrollment.
• Subject is scheduled to have an Abbott neurostimulation system implanted within 60 days of baseline.
• Subject has a baseline (with no stimulation) pain NRS of ≥ 6.

• Subject is enrolled, or intends to participate, in a competing clinical study, as determined by Abbott.
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical investigation or to comply with follow-up requirements.
• Subject has or is scheduled to receive an intrathecal pump.
• Subject is part of a vulnerable population.
• Subject has an existing implanted neuromodulation device to address their chronic pain.

• Men and Women ≥ 18 years of age.
• The patient has severe symptomatic mitral regurgitation meet criteria for the commercially available MitraClip.
• The patient also has documented paroxysmal, persistent, or permanent atrial fibrillation AND The patient meets the WATCHMAN labeling guidelines.
• The patient is eligible for short-term oral anticoagulation therapy with Warfarin or a direct oral anticoagulant.
• The patient or legal representative is able to understand and willing to provide written informed consent to participate in the trial.
• The patient is able and willing to return for required follow-up visit.

• Mitral valve anatomy not deemed suitable for TMVr.
• Moderate to severe mitral stenosis (mean gradient >10 mmHg or MVA <1.5 cm^2).
• Contraindication for short-term anticoagulation.
• The patient has intra-cardiac thrombus as visualized by TEE within 1 week prior to Watchman procedure.
• Prior occlusion of LAA.
• Implanted mechanical mitral valve.
• The patient requires long-term warfarin therapy due to:
  • Secondary to conditions such as prior arterial embolism or other indications such as pulmonary embolism or deep vein thrombosis within the previous 6 months;
  • The patient is in a hypercoagulable state;
  • Exclude the patient if per medical record documentation the patient meets any of the following criteria:
    • Thrombosis occurring at under 40 years age;
    • Idiopathic or recurrent VTE (venous thromboembolism;
    • Thrombosis at an unusual site (cerebral veins, hepatic veins, renal veins, IVC, mesenteric veins);
    • Family history of VTE or of inherited prothrombotic disorder, recurrence/extension of thrombosis while adequately anti-coagulated.
• The patient is actively enrolled in another trial of a cardiovascular device or an investigational drug (post-market study and registries are acceptable).
• The patient is pregnant, or pregnancy is planned during the course of the investigation if patient is of child bearing potential.
• Any clinically significant medical condition or presence of any laboratory abnormality performed prior to randomization that is considered by the investigator to be clinically important and could interfere with the conduct of the study or not meeting procedure guidelines for WATCHMAN or TMVr with MitraClip.
• The patient has a life expectancy of less than one year.

• 18 years of age or older at time of consent.
• Practicing Health Care Provider at Mayo Clinic.
• Not pregnant by subject self-report at time of consent.
• Have the ability to provide informed consent.
• Have the ability to complete all aspects of this trial.
• Have access to a  iPhone, iPad, or Android device.
• Have no contraindicating comorbid health condition which would interfere with the proper use of the Muse-S™ system,  as determined by the clinical investigators.

• Used an investigational drug within the past 30 days.
• Currently (within the past 3 weeks) been practicing mindfulness training on a weekly/regular basis.
• Currently (within 3 weeks) been enrolled in another clinical or research program (e.g., CAM) which intervenes on the patients’ QOL, or stress.
• An unstable medical or mental health condition as determined by the physician investigator.

• Males and females, at least 40 years of age, capable and willing to provide informed consent
• Patient must have received a diagnosis of COVID-19 infection within the last 24 hours
• Outpatient setting (not currently hospitalized or under immediate consideration for hospitalization)
• Patient must possess at least one of the following high-risk criteria:
  • 70 years or more of age, obesity (BMI ≥ 30 kg/m2)
  • Diabetes mellitus
  • Uncontrolled hypertension (systolic blood pressure ≥150 mm Hg)
  • Known respiratory disease (including asthma or chronic obstructive pulmonary disease)
  • Known heart failure
  • Known coronary disease
  • Fever of ≥38.4°C within the last 48 hours
  • Dyspnea at the time of presentation
  • Bicytopenia
  • Pancytopenia
  • The combination of high neutrophil count and low lymphocyte count
• Female patient is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine device (IUD)) throughout the study and for 30 days after study completion
• Patient must be able and willing to comply with the requirements of this study protocol.

• Patient currently hospitalized or under immediate consideration for hospitalization
• Patient currently in shock or with hemodynamic instability
• Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhea or malabsorption
• Patient with pre-existent progressive neuromuscular disease
• Estimated Glomerular filtration rate (eGFR), using the MDRD equation for all subjects being considered for enrollment, with a cut-off of < 30 mL/m in/1.73m2
• Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease
• Female patient who is pregnant, or breast-feeding or is considering becoming pregnant during the study or for 6 months after the last dose of study medication
• Patient currently taking colchicine for other indications (mainly chronic indications represented by Familial Mediterranean Fever or gout)
• Patient with a history of an allergic reaction or significant sensitivity to colchicine
• Patient undergoing chemotherapy for cancer
• Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

• Female with age ≥ 20 years.
• Liver biopsy documenting AGT activity below the normal reference range confirming PH1 OR Liver biopsy documenting GR/HPR activity below the normal reference range confirming PH2.
• Molecular genetic analysis (DNA testing) confirming a mutation known to cause PH1, PH2, or PH3; Homozygosity or compound heterozygosity of mutations of AGXT, GRHPR, or HOGA1 genes.
• Urinary oxalate excretion of greater than 0.8 mmol/1.73 m2/day (>70 mg/1.73 m2/day) in the absence of a gastrointestinal disease known to cause hyperoxaluria (enteric hyperoxaluria).
• If the patient presented in end stage renal failure, and neither a liver biopsy or mutational analysis were obtained, 5a and 5b must be fulfilled along with at least one of the criteria in 5c.
• Pre-dialysis plasma oxalate greater than 60 µmol/L; AND
• Renal biopsy confirming extensive oxalate deposition.
• Evidence of systemic oxalosis (at least one of the following criteria):
  • retinal oxalate deposits;
  • oxalate deposits in bone marrow, skin, or other tissue (histologically confirmed);
  • nephrocalcinosis;
  • calcium oxalate nephrolithiasis.

• Unwilling or unable to provide consent/assent.
• Patients unable or unwilling to provide medical record information.

• Men or women age ≥ 18.
• History of effort-induced anginal symptoms and currently experiencing angina at least 3 times per week, despite maximally tolerated doses of antianginal medications, statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and other medications thought to positively impact subjects with CMD.
• Diagnosis of CMD within 180 days prior to the first screening visit based on the following thresholds: coronary flow reserve (CFR) ≤ 2.5, coronary blood flow (CBF) response to acetylcholine ≤ 50%, myocardial perfusion reserve (MPR) or myocardial flow reserve (MFR) 25.
• *CCS class II, III, or IV chronic refractory angina as evaluated by the site.
• No obstructive disease on coronary angiogram within 6 months prior to or during screening. The following is allowed: a coronary artery stenosis less than 40% in the left main coronary artery, or a stenosis less than 50% in any other epicardial coronary artery.
• if subject is of childbearing potential, the subject must have a negative pregnancy test at screening and prior to mobilization and G-CSF treatment, and prior to receiving treatment. The subject agrees to employ adequate birth control measures for the duration of the study. Acceptable methods of birth control are: oral contraceptive tablets, hormonal implant device, hormonal patch, intrauterine device, diaphragm and contraceptive cream or foam, condom with spermicide, partner vasectomy, or abstinence.
• Subject is willing and able to comply with the requirements of the protocol.
• Any cardiovascular medical therapy must be at a stable dose for at least 30 days prior to the first screening visit and must be maintained at that dose throughout the duration of the study; cardiovascular therapy would generally include statins (unless not tolerated), ACE inhibitors, ARBs, beta blockers, calcium channel blockers, and/or ranolazine (unless ineffective or not tolerated).
• Able to provide signed informed consent.

• Myocardial infarction within 90 days prior to consent or between consent and treatment with CLBS16.
• Evidence of obstructive heart disease on screening angiogram or within 6 months prior to consent, including prior CABG at any time or history of PCI within 6 months prior to consent.
• Planned PCI or CABG.
• Diagnosis of other specific cardiac disease including:
  • aortic valve area < 1.0;
  • 3+ mitral regurgitation;
  • 3+ aortic insufficiency;
  • hypertrophic cardiomyopathy;
  • suspected or diagnosed Prinzmetal angina, or if acetylcholine provocation has been performed, significant coronary spasm as defined by more than 70% reduction in vessel diameter in response to acetylcholine;
  • severe myocardial bridging per investigator’s discretion;
  • Any anomalous coronary anatomy which could contribute to the subject’s angina.
• LVEF < 30%.
• Glomerular filtration rate < 30 mL/min/1.73m^2 (MDRD).
• Subject currently uses coumadin, dabigatran, apixaban, rivaroxaban, or edoxaban or plans to use one of these agents during the time frame of the trial.
• Subject has serious hypersensitivity or a history of adverse reaction to G-CSF or apheresis.
• Subject has a known allergy to mouse proteins
• Subject tests positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
• Subject with chronic inflammatory disease or autoimmune disease that has had an acute exacerbation of disease within the last 6 months, or subjects that are on immunosuppressive agents or in a chronic immunosuppressive state.
• Recent history of abuse or current abuser of alcohol or recreational drugs.
• Subject is pregnant or lactating at the time of signing the consent.
• Malignant neoplasm (other than adequately treated non-melanoma skin cancer or in situ cervical carcinoma) within 5 years prior to screening.
• Subject has participated in another clinical study within 90 days prior to signing the informed consent or is scheduled to participate in another clinical study during the course of the study. Observational studies in which the subject did not receive treatment or did not undergo procedures which may compromise this study’s data integrity may be allowable following Sponsor approval.
• History of sickle cell disease.
• Previous treatment with a CD34+ cell-based therapy.
• Any other condition which, in the opinion of the investigator, may preclude the subject from safe participation in the study or compromise data integrity

Eligibility last updated 10/4/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Patients with Multiple Myeloma with stable disease or currently in maintenance therapy.
• English speaking.
• Computer and internet access with video conferencing availability.

• Individuals < 18 years of age.
• Evidence of disease relapse at the post-transplant follow up visit.
• Patient not returning to Mayo Clinic Rochester for subsequent post-transplant follow up.

Eligibility last updated 2/2/22. Questions regarding updates should be directed to the study team contact.

• Males and Females ages 10-21 years.
• Cystic Fibrosis (CF) must be diagnosed.
• Ability to sign informed consent if they are 18 years or older.
• Written parental permission if age 10-17 years old.

Exclusion criteria:

• Active CF flare as determined by the primary CF team .
• Use of steroids.
• Inability to tolerate oral feedings.
• Prior intestinal surgery.
• Concern for allergy or intolerance to dextrose, fructose, or corn derivatives.

• Patient-reported history of cancer.
• Patient is able to read English.
• Patient-reported age of 18 years or older.

• Individuals under 18 years of age.

Eligibility last updated 5/17/22. Questions regarding updates should be directed to the study team contact.

• At least 6 years of age at the time of signing the informed consent/assent.
• Documented diagnosis of PH3, confirmed by genotyping (historically available genotype information is acceptable for study eligibility).
• 24-hour Uox excretion ≥ 0.7 mmol (adjusted per 1.73 m^2 BSA in participants < 18 years of age) in both collections performed in the screening period.
• Less than 20% variation between the two 24-hour urinary creatinine measurements in the screening period. Individuals who do not achieve < 20% variation between the 2 screening values may undergo a second round of urine collection. An extra 7 calendar days may be added to the screening window for participants to complete a second round of urine collection. Should potential participants again fail to achieve the within < 20% variation, they will be excluded from participation.
• Estimated GFR at screening ≥ 30 mL/min normalized to 1.73 m^2 BSA, calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula in participants aged ≥ 18 years (Levey & Stevens, 2010) or the multivariate formula by Schwartz in participants aged 6 to 17 years (Schwartz et al., 2012).
• History of at least one stone event within the last 12 months. Stone events are defined as any of the following:
  • Renal stone requiring medical intervention; e.g., outpatient procedures such as lithotripsy, or hospitalization or inpatient surgical intervention for confirmed stone-related pain and/or complications;
  • Stone passage with or without hematuria;
  • Renal colic requiring medication.
• Male or female
  • Male participants:
    • A male participant with a female partner of childbearing potential must agree to use contraception during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period.
  • Female participants:
    • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
    • Not a woman of childbearing potential (WOCBP);
    • A WOCBP who agrees to follow the contraceptive guidance for at least 12 weeks after the last dose of study intervention.
• Participant (and/or participant’s parent or legal guardian if participant is a minor [defined as patient < 18 years of age, or younger than the age of majority according to local regulations]) is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age of majority according to local regulations) must be able to provide written assent for participation.
• For children younger than 12 years of age, assent will be based on local regulations.

NON- BAVM recruit (living)

• Definite clinical HHT diagnosis (at least 3 Curacao criteria):
  • Spontaneous recurrent nosebleeds;
  • Mucocutaneous telangiectasia at characteristic sites (lips, oral cavity, fingers or nose);
  • Organ AVM (lung, brain, liver, renal, spinal or limb AVMs or GI telangiectasia);
  • An affected first-degree relative by same criteria.
• Genetic diagnosis of HHT.

BAVM recruit (living) or BAVM recruit (deceased)

• Presence of BAVM.
• Definite clinical HHT diagnosis (at least 3 Curacao criteria):
  • Spontaneous recurrent nosebleeds;
  • Mucocutaneous telangiectasia at characteristic sites (lips, oral cavity, fingers or nose);
  • Organ AVM (lung, brain, liver, renal, spinal or limb AVMs or GI telangiectasia);
  • An affected first-degree relative by same criteria.
• Genetic diagnosis of HHT.
• Able to provide informed consent in person or via a parent or legal authorize representative.

• None.

• Male or female must be ≥ 12 years.
• For adolescent participants only (12-17 years):  body weight > 40kg.
• Histologically confirmed unresectable or metastatic cutaneous melanoma.
• Documentation of BRAFV600 or NRAS mutation in tumor tissue prior to study treatment as determined by local assay or as determined by central pre-screening assessment performed at a Novartis designated laboratory.
• Previously treated for unresectable or metastatic melanoma.

Participants with NRAS mutation

• Participants must have received prior systemic therapy for unresectable or metastatic melanoma with an anti-PD-1/PD-L1 checkpoint inhibitor as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy, or locally-directed anti-neoplastic agents.
• Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant therapy with a checkpoint inhibitor.
• Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy.
• A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed.  Additional agents administered with a CPI are permitted.
• To rule out pseudo-progression, participants must have documented progressive disease as per iRECIST v1.1 while on/after treatment of with checkpoint inhibitor therapy.  Confirmation is not required for patients who remained on treatment > 6 months.

Patients with BRAFV600 mutant disease

• Participants must have received prior systemic therapy for unresectable or metastatic melanoma with a checkpoint inhibitor (CPI) either/and anti-PD-1/anti-PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally-directed anti-neoplastic agents.  Additionally, participants must have received targeted therapy with a RAFi as a single agent or in combination with a MEKi (+/- CPI allowed) as the last prior therapy. 
• Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant checkpoint inhibitors.
• Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy.
• A maximum of two prior lines of CPI-containing systemic therapy for unresectable or metastatic melanoma are allowed.  Additional agents with CPI are permitted.
• A maximum of one line of targeted therapy is allowed, and it must be most recent line of therapy.
• If a participant discontinued targeted therapy for reasons other than disease progression, a switch to another targeted therapy regimen is allowed.
• Participants must have documented progressive disease as per RECIST v1.1 while on/after treatment with targeted therapy. 
• Participants must have a site of disease amenable to repeated biopsies and must be willing to undergo a new tumor biopsy at baseline and during treatment according to the treating institution’s own guidelines and requirements for such procedure. For screening biopsy, exceptions may be made for patients who have undergone a fresh tumor biopsy out of the screening window and have received no intervening therapy, after discussion with the Novartis medical monitor.  Bone metastases are not acceptable as a site for biopsy.

• All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable.
• Insufficent bone marrow, hepatic renal function at the screening visit.
• Abnormal ECG as determined by the mean of a triple ECG and assessed locally.
• Cardiac disease or cardiac repolarization abnormality.
• Presence of ≥ CTCAE grade 2 toxicity (except alopecia) due to prior anti-cancer therapy.  Grade 2 endocrinopathies being treated with replacement therapy and are no longer symptomatic.
• History of current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

Eligibility last updated 10/14/21. Questions regarding updates should be directed to the study team contact.

• Newly diagnosed lymphoma before the start of therapy.

• Prior history of cancer or active autoimmune diseases requiring therapy.

• Diabetic and non-diabetic patients.
• ≥ 22 years of age for adults.
• For critically ill patients, medical status which requires treatment in a critical care unit, or medical status of patients in other units which is rated by a physician as critical:
  • Mayo site will enroll from the critically ill category in the OR setting;
  • Patients scheduled for cardiovascular surgery will be identified for study participation.
• For non-critically ill patients, medical status which requires treatment in a non-critical care unit, or medical status rated by a physician as non-critical.

• Subjects who do not meet Inclusion Criteria.

• Male of female subjects who are at least 18 years of age (inclusive) at the time of signing the Informed Consent Form (ICF).
• Have at least one measurable lesion per RECIST v1.1.
• Have formalin-fixed paraffin-embedded (FFPE) tissue available from a metastatic lesion; a tumor block or 25 unstained slides from an archived (within 2 years) or fresh tumor samples (core or punch needle biopsy) are acceptable.
• Documented tumor progression following no more than 3 lines of systemic chemotherapy, PARP inhibitor therapy or immunotherapy for metastatic disease, as appropriate. Of note, neoadjuvant and adjuvant therapy will not count as prior lines of therapy.
• Histologically confirmed diagnosis of inoperable locally advanced or metastatic TNBC defined as ER and progesterone receptor staining < 10%, and HER2 negative defined as IHC 0 to 1+.
• Documented Notch activation from tumor biopsy results from within the last 2 years from a commercially available NGS assay, LDT or other validated IUO clinical trial assay.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test.

• A known additional malignancy that is progressing or requires active treatment that is considered medically active and may interfere in the ability to detect responses in this subject. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that have undergone potentially curative therapy or in-situ cervical cancer.
• BC that, in the opinion of the investigator, is considered amenable to potentially curative treatment.
• Symptomatic central nervous system (CNS) metastases.
• Current or recent (within 2 months of IP administration) gastrointestinal (GI) disease or disorders that increase the risk of diarrhea, such as inflammatory bowel disease and Crohn's disease.
• Developed immune-mediated colitis with immunotherapy unless resolved to G1 or lower and without requirement of steroid treatment for at least 14 days prior to first dose of IP.
• Peripheral neuropathy Grade 2 for at least 14 days prior to first dose of IP.
• Evidence of uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral or anti-fungal therapy ≤ 7 days prior to administration of IP such as known active infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
• Unstable or severe uncontrolled medical condition (e.g., unstable cardiac or pulmonary function or uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the risk to the subject associated with his or her participation in the study.
• Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2.
• Abnormal organ and marrow function defined as:
  • neutrophils <1000/mm^3;
  • platelet count <75,000/mm^3;
  • hemoglobin < 8 g/dL;
  • total bilirubin > 1.5 upper limit of normal (ULN) (except known Gilbert's syndrome whereby the total bilirubin must be < 5 mg/dL);
  • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 ULN OR > 5 ULN for subjects with liver metastases;
  • creatinine clearance (CrCl) < 50 mL/min (calculation of CrCl will be based on acceptable institution standard);
  • uncontrolled triglyceride ≥ Grade 2 elevations per CTCAE v5.0 (> 300 mg/dL or > 3.42 mmol/L).
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 480 msec.
• Completed palliative radiation therapy < 7 days prior to initiating IP.
• Prior treatment with gamma secretase inhibitors.
• Last chemotherapy, biologic, or investigational therapy agent at least 4 weeks or 5 half-lives (whichever is shorter) prior to initiating IP; at least 6 weeks if the last regimen included BCNU or mitomycin C. Prior treatment with investigational monoclonal antibody will be reviewed case-by-case by the Sponsor.
• Receiving chronic systemic steroid therapy (in dosing exceeding 10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of IP. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
• Use of strong inhibitors of CYP3A4 within 1 week or 5 half-lives (whichever is longer) or strong inducers of CYP3A4 within 2 weeks or 5 half-lives (whichever is longer).
• Life expectancy is less than 3 months.

• Patients who have declined or elected to defer risk-reducing salpingo-oophorectomy (RRSO) after proper counselling to clearly explain the standard of care for BRCA1 mutation carriers (for the BLS with delayed oophorectomy arms) or patients who are undergoing RRSO (for the RRSO arm).
• At least one intact ovary and fallopian tube.
• Positive Clinical Laboratory Improvement Act (CLIA)-approved test results for pathogenic or likely pathogenic germline BRCA1 mutation in the patient herself. Documentation of the result is required.
• Premenopausal; defined as < 12 months of amenorrhea. However, for those patients with ≥ 12 months of amenorrhea who may be pre-menopausal or patients with a prior hysterectomy with at least one retained ovary/tube, levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and in the premenopausal range per local institutional standards will be acceptable.
• Concurrently planned or prior hysterectomy is permitted as long as at least one fallopian tube and one ovary had been retained.
• Transvaginal ultrasound (TVUS) and CA-125 within 180 days of registration.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.
• Patient must have negative urine pregnancy test within 14 days prior to registration based on local institutional policies.

• Women with a history of any prior cancer who have received chemotherapy within the past 12 months, hormonal therapy in the past 90 days, or radiotherapy to abdomen or pelvis at any prior time.
• Prior history of ovarian cancer, including low malignant potential neoplasms (LMP), primary peritoneal carcinoma, or fallopian tube carcinoma.
• Patients medically unfit for the planned surgical procedure.
• Patients with abnormal screening tests (TVUS, CA-125) suspicious for occult or gross pelvic malignancy or neoplasm within the past 180 days.
• An abnormal TVUS is defined as morphologic or structural variations suspicious for ovarian malignancy or complex cystic lesions (simple cysts < 5 cm in maximal diameter are not exclusionary).
• An abnormal CA-125 is defined as a level > 50 U/ml in this study population of premenopausal women if they are not current users of oral contraceptives.
• An abnormal CA-125 is defined as a level > 40 U/ml for premenopausal women who are current users of oral contraceptives.
• Women who are currently pregnant or plan to become pregnant in the future.

• Patients will be recruited during routine visits from the ocular oncology and glaucoma services.
• Cases: Subjects with an intraocular tumor undergoing primary treatment with plaque radiotherapy.
• Controls: Subjects with glaucoma undergoing filtering surgery (tube shunt or trabeculectomy).
• Age 18 years or older at the time of recruitment.
• Ability to understand and willingness to sign the informed consent documents.

• Under 18 years of age.
• Unable or unwilling to sign or understand the informed consent documents.
• Unwilling to participate in the research.
• Prior history of blepharoptosis or eyelid surgery before study enrollment.
• Not meeting the inclusion criteria.