Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 4/26/23. Questions regarding updates should be directed to the study team contact.

• Males and females aged ≥ 18 years (or ≥ 19 years according to local regulatory guidelines) at the time of screening.
• Has adequate organ and marrow function as defined in protocol.
• Measurable disease as per RECIST v1.1.
• ECOG performance status 0-1.
• Adverse events related to any prior chemotherapy, radiotherapy, immunotherapy, other prior systemic anti-cancer therapy, or surgery must have resolved to Grade ≤1, except alopecia and Grade 2 peripheral neuropathy.
• HIV infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease as defined in protocol.

• Has known active CNS metastases and/or carcinomatous meningitis.
• An active second malignancy.
• Has active or a known history of Hepatitis B or known active Hepatitis C virus infection.
• Has active tuberculosis or has a known history of active tuberculosis.
• Active or uncontrolled infections, or severe infection within 4 weeks before study treatment administration.
• History of chronic liver disease or evidence of hepatic cirrhosis, except patients with liver metastasis.
• Has an active autoimmune disease that has required systemic treatment in past 2 years.
• Previous immunotherapies related to mode of action of GI-102.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1.
• Administration of prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment.
• Radiotherapy within the last 2 weeks before start of study treatment administration, with exception of limited field palliative radiotherapy.
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1.
• Known hypersensitivity to any of the components of the drug products and/or excipients of GI-102.

Eligibility last updated 7/6/23. Questions regarding updates should be directed to the study team contact.

• Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma:
  • Cohort A: HER2-positive (by IHC 3+) and PD-L1-positive (by IHC with 22C3 CPS ≥ 1%), and non-MSI-H per central review 1%), and non-MSI-H per central review;
  • Cohort B: HER2-positive (by IHC 3+ or IHC 2+ in combination with FISH+) by local review. PD -L1 status is not required for enrollment. 
• Availability of formalin-fixed, paraffin-embedded tumor specimen, unstained slides or contemporaneous biopsy for tumor target testing.
• Eastern Cooperative Oncology Group performance status of 0 or 1, verified within 3 days of Day 1.
• Life expectancy ≥ 6 months.
• At least one radiographically measurable target lesion.
• Acceptable laboratory parameters and adequate organ function.

• Other malignancy that is progressing or required treatment within the past 5 years, with certain exceptions.
• Patients with MSI-H status by central test in Cohort A, or patients with known MSI-H status in Cohort B.
• History of allogeneic stem cell or tissue/solid organ transplant.
• Central nervous system metastases.
• Clinically significant cardiovascular disease, gastrointestinal disorders, pulmonary compromise.
• Prior neoadjuvant or adjuvant treatment with immunotherapy.

• Male and female.
• Aged 18
  •80 years old.
• Biopsy confirmed CD diagnosis (Pathology report confirmation by principal investigator).
• Self-reported adherence to a gluten-free diet for ≥ 12 months (documented by medical history).
• TG2 IgA antibody negative.
• Agree to maintain dosing of approved prescribed and OTC medications throughout the course of the study.
• Willing to take study treatment with each daily evening meal (e.g., dinner).
• Willing to take gluten foodstuff with each daily evening meal (e.g., dinner).
• If using a statin, willing to withhold statin therapy for 48 hours prior to in-clinic simvastatin ingestion and testing.
• Willing to maintain GFD for entire study duration.
• Willing to undergo multiple esophagogastroduodenoscopy procedures during the course of the trial.
• Access to a reliable telephone that would allow MSM dosing compliance telephone calls.
• Access to the internet via smartphone, tablet or computer device or equivalent to facilitate daily (end-of-day) symptom reporting.
• Willing to agree to minimal ingestion outside of three main daily meals.
• Willing to limit snacks outside the daily evening meal (e.g., dinner) to gluten-free snacks.
• Willing to not ingest grapefruit in any form (i.e., whole fruit, pulp, juice, etc.) during the 48 hour period prior to and during study visits 3 & 4.
• Willing and able to comply with all study procedures.
• Must read and understand English.
• Must sign informed consent.

• Active dermatitis herpetiformis lesions at the time of screening.
• History of any form of colitis.
• History of IgE-mediated reactions to wheat (i.e., “wheat allergy”).
• Any clinical contraindications to performing an endoscopy with intestinal biopsy.
• Received any systemic biologics (such as monoclonal antibodies or other protein therapeutics where the half-life overlaps with study start) within 6 months prior to study start.
• Taking any oral probiotic supplements (not including probiotics contained in commercially available food preparations) 6 months prior to entry.
• Use of any immunosuppressive medications (i.e., for chronic treatment of autoimmune disease or transplant-rejection prophylaxis) 6 months prior to entry.
• Use of systemic cortisone-like medications within 28-days prior to and during study treatment.
• History of alcohol abuse, illegal drug use (e.g. amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates) or medical and recreational cannabinoid use within the past 12 months.
• Laboratory values:
  • Elevated liver function tests (Alanine Aminotransferase [ALT], Aspartate Transaminase[AST],Alkaline Phosphatase [Alk Phos], or Gamma-Glutamyl Transferase [GGT]) > 2.5 times the upper limit of normal (ULN);
  • Total bilirubin > 1.5x ULN;
  • Serum creatinine > 1.5x ULN;
  • Hemoglobin < 10 g/dL or 100 g/L;
  • Calcium  < 8.0 mg/mL;
  • Platelet count< 75.0 x 109/L or 75,000/mm3;
  • Partial thromboplastin time (PTT) or prothrombin time (PT/INR) > 1.5 ULN;
  • Serum potassium < 3.0 mmol/L, > 5 mmol/L;
  • Total white blood cell count (WBC)  < 3.0 x 109/L or 3000/mm3;
  • Total lymphocyte < 1.0 x 109/L or 1000/mm3.
• Current untreated or active peptic ulcer disease, Grade B or greater esophagitis, motility disorders such as irritable bowel syndrome, functional dyspepsia, inflammatory bowel disease, and symptomatic GERD (gastroesophageal reflux disease) other than celiac disease.
• Women of Child Bearing Potential (WOCBP): positive urine pregnancy test.
• Unwilling to practice highly effective birth control (unless surgically sterilized or post-menopausal).
• Other than oral contraceptives, use of prescribed medications or over-the-counter medications that, in the opinion of the investigator might interfere with study results.
• Current use of anticoagulants (warfarin sodium, heparin, full-dose aspirin [325 – 650 mg/dose] or clopidogrel) during the 7-day period prior to randomization.
• Currently taking any medication(s) contraindicated for use with simvastatin that cannot be stopped 48 hours prior to visits 3 & 4 and restarted after visits 3 & 4, respectively.
• Received any experimental drug within 30 days of randomization, in the case of experimental biologics at least 6 months prior to randomization.
• The existence of any uncontrolled chronic disease or condition [for example HIV-AIDS, hepatitis, Type 1 or 2 diabetes, or cancer (other than skin cancer)], other than celiac disease.
• Uncontrolled complications of celiac disease, which, in the opinion of the investigator, could affect immune response or pose an increased risk to the patient (e.g. Type 1 diabetes or other autoimmune disease).
• Known allergy or hypersensitivity to any of the components of the placebo, IMGX003 (including sulfites), E. coli, or E. coli-derived proteins and simvastatin.
• Known adverse respiratory effects caused by sulfites.
• Inability to give informed consent.
• Any medical condition, other than celiac disease, which, in the opinion of the investigator, could adversely affect the patient’s participation in the trial.

• All tissue collected will be from sun-exposed sites.
• Adult patients, 18 years and older.

• Children, below 18 years of age.

• Male or female between 6 months through 36 months of age at the time of informed consent as clinical diagnosis of IS, confirmed by video-electroencephalogram (EEG) analysis, and hypsarrhythmia on EEG at screening according to the Burden of Amplitudes and Epileptiform Discharges (BASED) scale score.
• As assessed by the investigator has no or partial response to at least 2 out of the 3 therapies of adrenocorticotrophic hormone (ACTH), vigabatrin, and glucocorticoids (i.e. prednisolone), or has no or partial response to at least 1 out of the 3 therapies of ACTH, vigabatrin, and glucocorticoids and is contraindicated to and/or refused by the patient’s legal representative(s) for treatment with one or both other 2 therapies.
• Patient has general good health (defined as the absence of any clinically relevant abnormalities as determined by the investigator) based on physical and neurological examinations, medical history, normal renal function and electrocardiogram (ECG), and clinical laboratory values completed during the Screening Period visit (Visit 1).

• Patient considered by the investigator, for any reason (including, but not limited to, the risks described as precautions and warnings in the current version of the investigator’s brochure for investigational product) to be an unsuitable candidate to receive the investigational product.
• Patient has known or suspected allergy to the investigational product or apple juice.
• Patient has clinically significant renal impairment, defined as creatinine > mg/dL or blood urea nitrogen > 2 × upper limit of normal (ULN); clinically significant liver dysfunction, defined as total bilirubin ≥ 2 × ULN, or aspartate aminotransferase or alanine aminotransferase ≥ 3 × ULN; has clinically significant abnormal laboratory values; the investigator may deem the patient eligible if he/she judges the laboratory values to be not clinically significant.
• Patient has an ongoing or known history of human immunodeficiency virus infection, or chronic hepatitis B or C.
• Patient has a clinically significant abnormality on ECG that, in the opinion of the investigator, increases the safety risks of participating in the study.
• Patient has a neurodegenerative disorder as the underlying cause of IS.
• Patient has a known history of aspiration pneumonia within the past year.
• Patient has previously participated in another clinical study of the investigational product or received any investigational drug or device or investigational therapy within 30 days of study entry.
• Patient has received therapy with felbamate, cannabinoids, ketogenic diet or vagus nerve stimulation within 14 days of screening.
• Patient has received therapy with a medication known to be a CYP3A4 substrate and whose PK has been shown to be impacted in the presence of a CYP3A4 inhibitor within 14 days impacted in the presence of a CYP3A4 inhibitor within 14 days of screening.
• Patient has not remained at stables doses of all drugs used for treating epileptic seizures for at least 14 days prior to screening (except for rescue medications used for acute treatment of breakthrough seizures which are not known to be CYP3A4 substrates and whose PK has not been shown to be impacted in the presence of a CYP3A4 inhibitorist of CYP3A4 substrates]).
• Patient has a lethal or potentially lethal condition other than infantile spasms, with a significant risk of death before 18 months of age such as non-ketotic hyperglycinemia.
• Patient has an underlying metabolic disease associated with glucose intolerance (e.g., glucose transporter deficiencies).
• Patient has a body weight below 5 kg.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/4/23. Questions regarding updates should be directed to the study team contact.

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.

• Moderate or severe tricuspid valve regurgitation of primary or secondary etiology.
• Subject is adequately treated with medical therapy for heart failure 30 days prior to index procedure, including a diuretic.
• Heart Team determines patient is a recommended candidate for the VDyne System.
• Age 18 years or older.
• Clinical Screening Committee (CSC) and Imaging Core Labs confirm suitability for
• treatment with the VDyne System.

• Patient anatomy (cardiac and vascular) is not suitable for the VDyne System as assessed by Imaging Core Labs.
• Intolerance to procedural anticoagulation or post-procedural antiplatelet/anticoagulation regimen that cannot be medically managed.
• Hypersensitivity to nickel or titanium.

Clinical Exclusion Criteria (assessed by pre-procedural imaging):

• Left Ventricular Ejection Fraction (LVEF) < 30%.
• Severe RV dysfunction.
• Significant abnormalities of the tricuspid valve and sub-valvular apparatus.
• Sepsis including active infective endocarditis (IE) (within last 6 months).
• Right ventricular or atrial thrombus or vegetation.
• Severe tricuspid annular or leaflets calcification.
• Systolic pulmonary hypertension with systolic pulmonary artery pressure ≥70 mmHg.

CONCOMITANT PROCEDURES

• Significant coronary artery disease requiring treatment such as symptomatic, unresolved multi-vessel or unprotected left main coronary artery disease.
• Any planned surgery or interventional procedure within the period of 30 days prior to 30 days following the implant procedure. This includes any planned concomitant cardiovascular procedure such as CABG, PCI, pulmonary vein ablation, left atrial appendage occlusion, septal defect repair, etc.
• Unresolved severe symptomatic carotid stenosis (> 70% by ultrasound).
• Cardiac resynchronization therapy device or implantable pulse generator implanted within 60 days of planned implant procedure.
• Permanent pacing leads that will interfere with delivery or implantation of the VDyne Valve.
• Cardiogenic shock or hemodynamic instability requiring inotropes or mechanical support devices at the time of planned implant procedure.
• Prior tricuspid valve surgery or catheter-based therapy with permanent residual devices implanted that would preclude delivery or implantation of the VDyne Valve (e.g., valve replacement, edge to edge repair).
• Severe valvular heart disease requiring intervention other than the tricuspid valve.
• Known significant intracardiac shunt (e.g., septal defect) (PFO's without significant shunts are allowed).

COMORBIDITIES

• Cerebrovascular accident (stroke, TIA) within 6 months of treatment procedure.
• Severe lung disease (severe COPD or continuous use of home oxygen or oral steroids).
• Acute myocardial infarction (AMI) within 30 days.
• Significant renal dysfunction (eGFR<30 ml/min/1.73m^2) or on dialysis.
• End-stage liver disease (MELD > 11 / CHILD class C).
• Bleeding requiring transfusion within 30 days.
• Coagulopathy or other clotting disorder that cannot be medically managed.
• Chronic immunosuppression or other condition that could impair healing response.
• Any of the following: leukopenia, chronic anemia (Hgb < 9), thrombocytopenia, history of bleeding diathesis, or coagulopathy
• Unwilling to receive blood products.

General

• Known hypersensitivity or contraindication to procedural or post-procedural medications (e.g., contrast solution) which cannot be adequately managed medically.
• Life expectancy less than 12 months due to non-cardiac comorbidities.
• Treatment is not expected to provide benefit (futile).
• Current IV Drug user (must be free drug abuse for > 1 year).
• Pregnant, lactating or planning pregnancy within next 12 months. (female of child-bearing potential use two reliable contraceptive methods during the study -hormonal methods such as pill and condom).
• Vulnerable patient groups (minors, cognitively impaired persons, prisoners, persons whose willingness to volunteer could be unduly influenced by the expectation of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate, such as students, residents, and employees).
• Currently participating in an investigational drug or device trial that has not reached its primary endpoint or is likely to interfere with this study.
• Patient (or legal guardian) unable or unwilling to provide written informed consent before study-specific procedures are conducted.
• Patient unable or unwilling to comply with study required testing and follow-up visits.

Eligibility last updated 4/14/23. Questions regarding updates should be directed to the study team contact.

Children under the age of 18 and adults lacking the capacity to consent will not be included in this study.

• Individuals, ≥ 18 years of age.
• Previously registered to A151216.
• Central and/or local testing of EGFR with no EGFR exon 19 deletion or EGFR L858 R mutation.
• Central and/or local testing of ALK with no ALK rearrangement (failed testing is  considered negative).
• Central and/or local testing of PD-L1 immunohistochemistry (IHC) using one of the  following assays: DAKO 22C3, DAKO 28-8, or SP263.
  • Note: Local testing results of EGFR and ALK by a local Clinical Laboratory Improvement Act (CLIA) certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, or SP263 are acceptable for enrollment on A081801.
• Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration.
• Completely resected stage IB (≥ 4 cm), II or IIIA non-small cell lung cancer (NSCLC)  with negative margins (complete R0 resection).
• Patients will be staged according to  the 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2010.
  • Note: Patients with pathologic N2 disease, completely resected, are eligible; however, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population.
• Complete recovery from surgery. Registration to A081801 must be 30-77 days following surgery.
• No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis.
• No prior allogeneic tissue/solid organ transplant.
• Patients must NOT have uncontrolled intercurrent illness including, but not limited  to, serious ongoing or active infection, symptomatic congestive heart failure,  uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements.
• No current pneumonitis or history of (non-infectious) pneumonitis that required steroids.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral  therapy with undetectable viral load within 6 months are eligible for this trial.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1.
• No active auto-immune disease that has required systemic treatment within the last 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release  therapy for adrenal or pituitary insufficiency) is not considered a form of systemic  treatment.
• 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 ≤ 7 days prior to registration is required. 
• No patients with a "currently active" second malignancy that is progressing or has required active treatment within the last 3 years. Participants with non-melanoma skin  cancers or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) that  have undergone potentially curative therapy are eligible
• No hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients.
• No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella,  varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG),  and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed  virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed. 
• No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]  reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA]  [qualitative] is detected) infection.
• Required initial laboratory values:
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3; 
  • Platelet count ≥ 100,000/mm^3;
  • Hemoglobin ≥ 8 gm/dl;
  • Calculated (Calc.) creatinine clearance ≥ 45 mL/min;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 x upper limit  of normal (ULN).

• Individuals < 18 years of age.

• Patients who have previously undergone anterior thalamic nucleus deep brain stimulation (DBS) for refractory epilepsy.

• Contraindication to MRI; prior brain resective surgery or large area of brain tissue loss (e.g., large area infarction).

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/17/23. Questions regarding updates should be directed to the study team contact.

• Participant must be aged 6 to 17 years, inclusive, at Screening (Visit 1).  
• Participants who have been diagnosed with HES for at least 6 months prior to enrolment (Visit 2).
• A history of 2 or more HES flares within the past 12 months prior to Screening (Visit  1).  
• Participants must have blood eosinophil count ≥ 1000 cells per microliter (/mcL) present at Screening.
• Participants must be on a stable dose of HES therapy for the 4 weeks prior to the  first dose of mepolizumab (Visit 2).
• Male and/or female.
• Signed written informed consent.

• Life-threatening HES or life-threatening HES co-morbidities.
• Other concurrent medical conditions that may affect the participant's safety.
• Eosinophilia of unknown significance.
• Fusion tyrosine kinase gene translocation [FIP1L1.
• Platelet-derived Growth Factor  Receptor (PDGFRα) (F/P)] positivity.
• Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA).
• Participants with chronic or ongoing active infections requiring systemic treatment, as well as participants who have experienced clinically significant infections due to viruses, bacteria, and fungi within 4 weeks prior to enrolment (Visit 2).
• Participants with a pre-existing parasitic infestation within 6 months prior to  enrolment (Visit 2).
• Participants with a known immunodeficiency (e.g., Human immunodeficiency virus [HIV]),  other than that explained by the use of OCS or other therapy taken for HES
• Participants with documented history of any clinically significant cardiac damage  prior to Screening (Visit 1) that, in the opinion of the investigator, would impact the participant's participation during the study.
• Participants with a history of or current lymphoma.
• Participants with current  malignancy or previous history of cancer in remission for less than 12 months prior to  Screening (Visit 1).
• Participants who are not responsive to OCS based on clinical response or blood  eosinophil counts.  
• Participants who have previously received mepolizumab in the 4 months prior to  enrolment (Visit 2).
• Participants receiving non-oral systemic corticosteroids in the 4-week period prior to  enrolment (Visit 2).  
• Participants who have received any other monoclonal antibodies within 30 days or 5 half-lives, whichever is longer, of enrolment (Visit 2).
• Participants who have received treatment with an investigational agent (biologic or  non-biologic) within the past 30 days or 5 drug half-lives, whichever is longer, prior to enrolment (Visit 2).  
• Use of candidate Coronavirus disease 2019 (COVID-19) vaccines that have not received  limited, accelerated, or full authorization/approval, and are only in use as part of a  clinical trial.  
• Participants who are currently participating in any other interventional clinical study.
• Participants with any history of hypersensitivity to any monoclonal antibody (including mepolizumab).
• Evidence of clinically significant abnormality in the hematological, biochemical, or urinalysis screen from the sample collected at Screening (Visit 1), that could put the participant's safety at risk by participating in the study, as judged by the  investigator.

Unless specified otherwise, all eligibility criteria time-intervals are assessed with respect to the screening visit.

• Age 18 to 70 years.
• Living donor / deceased donor kidney transplant recipients ≥ 6 months from time of transplant.
• Diagnosis of CABMR determined by kidney biopsy and the presence of human leukocyte antigen (HLA) donor specific antibodies (DSA) using single-antigen bead-based assays.
  • NOTE: If conducted within 6 months (+ 3 weeks) of the start of the Screening Period, the biopsy and DSA analysis do not need to be repeated at Screening. To be considered for determination of study eligibility, the biopsy and DSA analysis must be performed and should occur at least 2 months ± 2 weeks after the end of any prior treatment for ABMR (including CABMR) or TCMR, in order to show continuing CABMR and presence of HLA DSA. In addition, treatments for ABMR or TCMR are not allowed within 3 months of the start of Screening. The following histopathologic and serologic diagnostic criteria (based on Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion:
    • Morphologic evidence of chronic tissue injury, as demonstrated by transplant glomerulopathy (TG) (cg > 0). Biopsies without evidence of chronic tissue injury on light microscopy, but with glomerular basement membrane double contours on electron microscopy (cg1a) are eligible;
    • Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following.
    • Linear complement component 4d (C4d) staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections);
    • At least moderate microvascular inflammation ([g + ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient; and must be ≥ 1.
  • NOTE: The local pathologist’s diagnosis must be reviewed by a central pathologist to confirm eligibility for entry into the study. Biopsies with other histopathologic changes (e.g., BKV nephropathy or recurrent glomerulonephritis) may be eligible if concurrent CABMR changes (as detailed above) are present and determined to be the predominant cause of renal dysfunction.
  • Serologic evidence of circulating HLA DSA. NOTE: The local laboratory DSA results must be reviewed and confirmed by the central HLA reviewer during the Screening Period.
• Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures.

• Participant is unable or unwilling to comply with study procedures in the opinion of the investigator.
• Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient.
• Treatment for ABMR (including CABMR) or TCMR within 3 months of the start of Screening.
• Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months of the start of Screening.
• Treatment with mTOR inhibitors within 4 weeks of the start of Screening.
• Biopsy indicating predominant cause of renal dysfunction caused by pathology other than CABMR.
• Impaired renal function due to disorders in the transplanted allograft (eg, renal artery stenosis, hydronephrosis).
• eGFR < 25 mL/min/1.73 m^2 or > 65 mL/min/1.73 m^2 (MDRD4).
• Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (UACR) ≥ 2200 mg/g (≥ 220 mg/mmol). If spot UACR is above defined limits, a single repeat test can be performed on a separate day to confirm ineligibility.
• Pregnant, breastfeeding, or unwillingness to practice adequate contraception (eg, a highly effective or acceptable method of contraception) during the study and for 5 months after last dose of IP.
• History of anaphylaxis or known hypersensitivity to clazakizumab or to any constituent of the drug product.
• Abnormal liver function tests (LFTs [alanine aminotransferase (ALT) / aspartate aminotransferase (AST) / bilirubin > 1.5 x upper limit of normal]) or other significant liver disease.
• History of active tuberculosis (TB).
• History of latent TB (eg, positive QuantiFERON-TB test) without history of active TB unless subject has completed a full course of prophylactic treatment.
• History of human immunodeficiency virus (HIV) infection or positive for HIV.
• Seropositive for hepatitis B surface antigen (HBsAg).
• Hepatitis C virus (HCV) RNA positive.
• Known EBV mismatch (at time of transplant): donor seropositive, recipient seronegative.
• History of gastrointestinal (GI) perforation; diverticular disease defined as clinically significant diverticulosis (except if disease has been fully excised) or diverticulitis (except if disease has been fully excised); or inflammatory bowel disease (except fully excised ulcerative colitis).
• Neutropenia (< 1000/mm^3 ) or thrombocytopenia (< 50,000/mm^3 ).
• Active infections requiring systemic antimicrobial agents and unresolved prior to Screening.
• History of or current invasive fungal infection or other opportunistic infection, including (but not limited to) the following: a nontuberculous mycobacterial infection, aspergillosis, pneumocystosis, and toxoplasmosis.
• Active viral infections such as BKV, CMV, or EBV based on polymerase chain reaction (PCR) testing. Active infection is defined as a test result ≥ lower limit of quantification (LLOQ).
• Current or recent (within 3 months) participation in an interventional trial.
• Administration of a live vaccine within 6 weeks of the start of screening, including but not limited to the following:
  • Adenovirus;
  • Measles, mumps, and rubella;
  • Oral polio;
  • Oral typhoid;
  • Rotavirus;
  • Varicella zoster;
  • Yellow fever.
• History of alcohol or illicit substance (including marijuana) abuse.
• Present or previous (within 3 years) malignancy except for basal cell carcinoma, fully excised squamous cell carcinoma of the skin, or nonrecurrent (within 5 years) cervical carcinoma in-situ.
• Presence of a condition or abnormality (i.e., clinically significant endocrine, autoimmune, metabolic, neurological, psychiatric / psychological, renal, GI, hepatic, and hematological or any other system abnormalities that are uncontrolled with standard treatment) that in the opinion of the investigator would compromise the safety or life expectancy of the patient or the quality of the data.
• History of intolerance to trimethoprim and / or sulfamethoxazole. This criterion does not apply if subject is already taking another suitable investigator-approved alternative for PJP prophylaxis, or if subject is willing to begin taking an investigator-approved alternative prophylactic therapy at least 1 week prior to the Day 1 Baseline Visit (Visit 2).
• Prior exposure to clazakizumab, TCZ, or other IL-6 / IL-6R blockers.
• ABO-incompatible transplant recipient.
• Severe hypogammaglobulinemia (defined as immunoglobulin G (IgG) < 400 mg/dL).
• Prior (within 2 years of the start of Screening) exposure to proteasome inhibitors (e.g., bortezomib).
• Active infection with coronavirus disease 2019 (COVID-19):
  • Subject not known to have been previously infected with COVID-19 must have a negative PCR test during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible. If subject is unwell with symptoms suggestive of COVID 19 disease but PCR test is negative, other causes for symptoms must be ruled out to determine subject eligibility;
  • Subject known to have been previously infected with COVID-19 must meet all the following conditions:
  • Must be without symptoms attributable to COVID-19 for at least 1 month before the start of screening and have had 2 consecutive negative PCR tests at least 24 hours apart (either prior to or during screening) to confirm recovery. If the subject has tested negative > 3 months before start of screening, the subject must have a negative PCR test during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible;
  • Must be re-established on background immunosuppressants for at least 2 weeks prior to the start of Screening.

• Admitted to a hospital with symptoms suggestive of Coronavirus Disease 2019 (COVID-19) and requires ongoing medical care.
• Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Male or non-pregnant female adult ≥ 18 years of age at time of enrollment.
• Illness of any duration and has laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g., Nucleic Acid Amplification Test [NAAT], antigen test) in any respiratory specimen, or saliva 5 times the upper limit of normal.
• Illness of any duration, and requiring, just prior to randomization, supplemental oxygen (any flow), mechanical ventilation or ECMO (ordinal scale category 5, 6, or 7). 
• Women of childbearing potential must agree to either abstinence or use at least one acceptable method of contraception from time of screening through 5 months post study IP dosing.
  • Note: acceptable methods include barrier contraceptives (condoms or diaphragms) with spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and surgical sterilization. 
• Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through day 29. 

• ALT or AST > 5 times the upper limit of normal. 
• Subjects with a low glomerular filtration rate (eGFR), specifically:
  • Subjects with a glomerular filtration rate (eGFR) 20-30 mL/min are excluded unless in the opinion of the principal investigator (PI), the potential benefit of participation outweighs the potential risk of study participation;
  • All subjects with a glomerular filtration rate (eGFR) < 20 mL/min (including hemodialysis and hemofiltration) are excluded.
• Pregnancy or breast feeding.
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of enrollment.
• Allergy to any study medication.
• Received five or more doses of remdesivir prior to screening.
• Received two or more doses of > 60 mg of prednisone or equivalent in the 7 days prior to screening.
• Received small molecule tyrosine kinase inhibitors, including Janus kinase (JAK) inhibitors (e.g., baricitinib, ibrutinib, acalabrutinib, imatinib, gefitinib), in the 4 weeks prior to screening.
• Received monoclonal antibodies targeting cytokines (e.g., tumor necrosis factor (TNF) inhibitors, anti-IL-1 [e.g., anakinra, canakinumab], anti-IL-6 [e.g., tocilizumab, sarilumab, sitlukimab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.
• Received monoclonal antibodies targeting B-cells (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.
• Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g., sargramostim) within 2 months prior to screening.
• Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with lenzilumab is larger than the risk of Coronavirus Disease 2019 (COVID-19).
• Received any live vaccine in the 4 weeks prior to screening.
• Known active tuberculosis.
• Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated hepatitis C (HCV) infection.
• History of pulmonary alveolar proteinosis (PAP).
• Has a malignancy currently receiving immunosuppressive chemotherapy, immunodeficiency, uncontrolled opportunistic infection, or uncontrolled cirrhosis.
• Has a medical condition that could, in the judgment of the investigator, limit the interpretation and generalizability of trial results.
• Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
• Previous participation in an ACTIV-5/Big Effect Trial (BET).

• Esophageal Cancer any stage
• Age >18 years old
• Willing and able to provide consent
• No prior history of neoadjuvant therapy for the esophageal cancer

• Age <18 years old
• Unable to provide consent

Inclusion Criteria:

• Patients fulfilling the following criteria will be eligible for entry into this study:

  1. Patients with de novo MDS who have, or have previously had, Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is NOT a requirement.
  2. Patients must have fewer than 20% marrow blasts at the time (within 30 days) of registration and consent.
  3. Patients may have received prior therapy for the treatment of MDS, including but not limited to: growth factor, transfusion support, immunomodulatory (IMID) therapy, DNA hypomethylating therapy or cytotoxic chemotherapy prior to trial registration.
  4. Age 50.0-75.0 years.
  5. Karnofsky performance status > 70 or Eastern Cooperative Oncology Group (ECOG) ≤ 1 (see comparison scale in Appendix D).
  6. Patients are eligible if no formal unrelated donor search has been activated prior to enrollment. Patients who have started a sibling donor search or who have found a matched sibling donor are eligible.

  7. Patients and physicians must be willing to comply with treatment assignment:

     1. No intent to proceed with alloHCT using donor sources not specified in this protocol, including Human leukocyte antigen (HLA)-mismatched related or unrelated donors < 6/6 HLA related matched or < 8/8 HLA unrelated matched) or umbilical cord blood unit(s).
     2. No intent to use myeloablative conditioning regimens.
     3. Intent to proceed with RIC alloHCT if a matched sibling or matched unrelated donor is identified. There is no requirement as to the timing of the transplantation.
  8. Patients must be considered to be suitable RIC alloHCT candidates at the time of enrollment based on medical history, physical examination and available laboratory tests. Specific testing for organ function is not required for eligibility but, if available, these tests should be used to judge eligibility.
  9. Signed informed consent

• Patients with the following will be ineligible for registration onto this study:

  1. Therapy-related MDS
  2. Current or prior diagnosis of AML
  3. Uncontrolled bacterial, viral or fungal infection
  4. Concurrent malignancy other than superficial squamous cell or basal cell carcinoma of the skin
  5. Prior autologous or allogeneic HCT
  6. Human Immunodeficiency Virus (HIV) infection
  7. Fertile patients unwilling to use contraceptive techniques
  8. Patients with psychosocial conditions that would prevent study compliance

Inclusion Criteria
•Core Part:

• Signed informed consent/assent must be obtained prior to participation in the study
• Between 10 to < 18 years of age (i.e., have not yet had their 18th birthday) at randomization.
• A diagnosis of MS as defined by the consensus definition for pediatric MS (Thompson et al 2018).
• Expanded Disability Status Scale (EDSS) score of 0 to 5.5 (inclusive) at Screening.
• At least one MS relapse/attack during the previous year or two MS relapses in the previous two years prior to screening or evidence of one or more new T2 lesions compared to prior MRI conducted within 12 months prior to randomization (including screening MRI) or one or more Gd-enhancing T1 lesions on MRI conducted within 12 months prior to randomization.

Inclusion Criteria
•Extension Part:

• Re-consent / assent must be obtained prior to E-Day 1 in the Extension part.
• Participants who complete the Core Part on randomized double-blind treatment.

Exclusion Criteria
•Core Part:

• Participants with progressive MS.
• Participants meeting the definition of ADEM (Krupp et al 2013); participants meeting criteria for neuromyelitis optica (Wingerchuk et al 2006) or tested positive for aquaporin 4 (AQP4) at Screening; participants tested positive for anti-MOG at Screening.
• Participants with widespread and symmetric white matter alterations in the Screening MRI suggestive of other demyelinating disorders (e.g., metabolic disorders, mitochondrial disorders).
• Homozygosity for CYP2C9*3, or refusal to test for CYP2C9.
• Participants with an active, chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g. Sjögren’s disease, systemic lupus erythematosus) or with a known immunodeficiency syndrome (acquired immunodeficiency syndrome (AIDS), hereditary immune deficiency, drug-induced immune deficiency) or tested positive for HIV at Screening.
• Participants with neurological symptoms consistent with PML or confirmed PML.
• Participants diagnosed with macular edema during the Screening period.
• Participants with severe active systemic bacterial, viral or fungal infections, including tuberculosis.
• Participants with any severe cardiac disease or significant findings on the screening ECG, such as:
  • History of symptomatic bradycardia or recurrent syncope;
  • Known ischaemic heart disease;
  • History of congenital heart disease (except conditions such as small patent ductus arteriosus, atrial septal defect, ventricular septal defect, or an ECG or rhythm abnormality, which have been assessed by a pediatric cardiologist and considered to be clinically insignificant);
  • Cerebrovascular disease;
  • History of myocardial infarction;
  • Congestive heart failure;
  • History of cardiac arrest;
  • Resting (sitting) heart rate < 55 bpm (in participants 12 years or older) and <60 bpm (in participants below 12 years);
  • Severe untreated sleep apnea;
  • Sick sinus syndrome or sino-atrial heart block;
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) ;
  • QTcF interval > 450 msec in males and > 460 msec in females or relevant risk factors for QT prolongation (e.g., hypokalaemia, hypomagnesemia, congenital QT prolongation) or treatment with QT prolonging drugs with a known risk of Torsades de pointes or history of familial long QT syndrome or known family history of Torsades de Pointes;
  • Uncontrolled arterial hypertension despite prescribed medications.
• Participants with any pulmonary conditions, as determined by the investigator, including severe asthma defined as per the 2010 World Health Organization (WHO) uniform definition on severe asthma (Bousquet et al 2010);
• Participants with any of the following neurologic/psychiatric disorder:
  • History of any type of epileptic seizure(s) as well as psychogenic non-epileptic seizure(s) during the past 12 months before screening;
  • Ongoing substance abuse (drug or alcohol) or any other factor (i.e., serious psychiatric condition) that may interfere with the participant’s ability to cooperate and comply with the study procedures;
  • History of clinically significant CNS disease (e.g., stroke, traumatic brain or spinal injury, history or presence of myelopathy) or neurological disorders which may mimic MS.
• Participants with a score of “yes” on item 4 or item 5 of the Suicidal Ideation section of the C‑SSRS, if this ideation occurred in the past 6 months, or with a score of “yes” on any item of the Suicidal Behavior section, except for “Non-Suicidal Self Injurious Behavior”, if this behavior occurred in the past 2 years.
• Any history of malignancy of any organ system
• Any of the following conditions or treatments that may impact the safety of the participant:
  • Participants with any history of or active severe respiratory disease as determined by the investigator;
  • Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of Gilbert’s syndrome;
  • Participants with severe renal insufficiency (GFR <30 mL/min/1.73 m^2).
• Any of the following abnormal laboratory values as confirmed by the central laboratory prior to first study drug administration:
  • Positive results of screening period testing for serological markers for hepatitis A, B, C and E indicating acute or chronic infection;
  • Anti-HAV IgM positive;
  • If HBs Ag and/or anti-HBc positive, HBV-DNA Polymerase Chain Reaction (PCR) will be performed (if negative, participant can be included);
  • If anti-HCV antibody positive, HCV-RNA PCR will be performed (if negative, participant can be included);
  • If anti- HEV IgM or IgG positive, HEV-RNA PCR will be performed (if negative, participant can be included).

• Provision of signed and dated informed consent form.
• Subject is 18 years of age and older.
• Subject has a diagnosis of unresectable Stage 3 pancreatic adenocarcinoma cancer cytologically or pathologically confirmed per American Joint Committee on Cancer (AJCC) staging criteria.
• Subject has a tumor evaluated as Stage 3 according to National Comprehensive Cancer Network (NCCN) guidelines, based on radiographic imaging or exploratory surgery.
• Maximum axial and anterior to posterior tumor dimension of ≤3.5cm, after receiving three months of treatment with the modified FOLFIRINOX regimen.
• Subject has received 3 months of treatment with the modified FOLFIRINOX regimen.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Subject has an American Society of Anesthesiologists (ASA) classification of physical health status of 1, 2, 3 or 4.

• Subjects who are or may be pregnant as determined by a positive pregnancy test or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of chemotherapy.
• Subjects who are unable to tolerate general anesthetic with full skeletal muscle blockade.
• Subjects who are actively bleeding, anticoagulated, coagulopathy, or have any of the following hematology results:
  • hemoglobin less than 10 g/dL without the support of growth factors or transfusion; absolute neutrophil count less than 1500 cells/mL; or
  • platelet count less than 100,000.
• Subjects with the presence of implanted cardiac pacemakers, defibrillators, electronic devices or implanted devices with metal parts in the thoracic cavity at the time of IRE.
• Subjects with history of epilepsy or other neurological disease.
• Subjects with renal, cardiac, liver, or hematological abnormalities of concern to the investigator.
• Subjects with Stage 3, 4, or 5 chronic kidney disease.
• Subjects receiving IRE for margin accentuation.
• Subjects who at 3 months after FOLFIRINOX treatment have evidence of disease progression.
• Participation in another interventional trial for pancreatic cancer.
• Subjects who did not meet study defined criteria for adequacy of induction treatment at the end of the 3 months.

Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this
study:
1. At the time of randomization, requires supplemental oxygen ≥2 LPM due to hypoxemia.
Hypoxemia can be defined by meeting at least one of the following criteria:
 
•SpO2 <92% on or off supplemental oxygen
  - Respiratory failure necessitating mechanical or non-invasive ventilation (CPAP or Bi-PAP)
  - Written declaration from Investigator that subject is clinically hypoxemic and removal of oxygen supplementation would not be considered clinically appropriate for the purpose of measuring SpO2 while on room air
   Note: Documentation of hypoxemia prior to or during the most recent oxygen supplementation must be available in source.
   Note: Subjects who also require invasive mechanical ventilation (MV) or non-invasive positive pressure ventilation (CPAP or bi-PAP) are eligible, although ventilator support is not mandatory
2. Immunocompromised, as defined by one or more of the following:
  - Received an autologous or allogeneic hematopoietic stem cell transplantation (HSCT) at any time in the past
 
•Received a solid organ transplant at any time in the past
  - Has been or is currently being treated with chemotherapy for hematologic malignancies (e.g., leukemia, myeloma, lymphoma) and/or solid tumor malignancies (e.g., lung, breast, brain cancer) at any time in the past
 
•Has an immunodeficiency due to congenital abnormality (only applicable to subjects age < 18 years old) or pre-term birth (only applicable to subjects age ≤ 2 years old)
3. Has, within 3 days prior to randomization, a confirmed LRTI with a sialic acid dependent respiratory virus (SAD-RV, see definition). This can be confirmed by:
 
•bronchoalveolar lavage (BAL) positive for SAD-RV
 
•lung biopsy positive for SAD-RV
 
•chest imaging with a new or worsening finding of pulmonary infiltrate, bronchiolitis, or pneumonitis temporally associated with an upper respiratory tract sample (e.g., tracheal aspirate, sputum, nasopharyngeal swab (NPS), nasopharyngeal wash) positive for SADRV
   Note: These requirements can be fulfilled by results from samples and/or chest imaging that are collected/performed locally as per standard of care within 3 days prior to randomization.
   Note: For all subjects, after obtaining informed consent but within 3 days prior to randomization, a separate nasopharyngeal swab sample will be collected and sent to thecentral laboratory for confirmation of a SAD-RV. The results from the central lab analysis are not required to initiate the subject on study treatment.
4. If female, subject must meet one of the following conditions:
 
•Not be of childbearing potential, defined as one or more of the following conditions:
     - Premenarchal
     - Postmenopausal for at least 1 year
     - Surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
 
•Be of childbearing potential and meet all of the following criteria:
     - Has a negative urine or serum pregnancy test (beta-human chorionic gonadotropin) at screening
     - Agrees to practice an acceptable method of contraception (or meets criteria for waiving contraception) from screening until at least 30 days after last dose of study medication (see Section 8.10.1 for details)
Additional contraception requirements may need to be followed according to local regulations and/or requirements.
5. Non-vasectomized males are required to practice effective birth control methods (see Section 8.10.1) from screening until at least 30 days after last dose of study medication
6. Capable of understanding and complying with procedures as outlined in the protocol as judged by the Investigator and able to sign informed consent form prior to the initiation of any screening or study-specific procedures. Subjects must have the ability to return to the hospital to comply with required procedures if they are discharged during the study.
   Note: For subjects, including minors and patients with medical incapacity or impaired consciousness such that they are not able to give fully informed voluntary consent, the subjects' legal representative (parent, guardian or surrogate) must sign an institutional review board (IRB)/independent ethical committee (IEC)-approved informed consent document prior to the initiation of any screening or study-specific procedures. Minor subjects must also sign an IRB/IEC-approved assent form unless not required per local and institution regulations
 

 Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1. Subjects may not be on hospice care or, in the opinion of the investigator, have a low chance of survival during the first 10 days of treatment
2. Subjects with Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), or Alkaline Phosphatase (ALP) ≥3x ULN and Total Bilirubin (TBILI) ≥2x ULN
Note: Subjects with ALT/AST/ALP ≥ 3x ULN AND TB ≥2x ULN that have been chronically stable (for >1 year on more than one assessments) due to known liver pathology including malignancy (primary or metastasis), chronic medications, transplantation, or chronic infection will not be excluded
3. Female subjects breastfeeding or planning to breastfeed at any time through 30 days after the last dose of study drug
4. Subjects taking any other investigational drug used to treat pulmonary infection.
5. Psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the principal investigator, would affect subject safety and/or compliance
6. Subjects with known hypersensitivity to DAS181 and/or any of its components

7. Subjects with severe sepsis due to either their baseline SAD-RV infection or a concurrent viral, bacterial, or fungal infection and meet at least one of the following criteria:
   - Has evidence of vital organ failure outside of the lung (e.g., liver, kidney)
   - Requires vasopressors to maintain blood pressure

• Clinical signs and symptoms consistent with the diagnosis of an acute ischemic stroke, and subject belongs to one of the following subgroups:
  • Subject has failed IV t-PA therapy;
  • Subject is contraindicated for IV t-PA administration;
  • IV-tPA given within 3 hours of symptom onset.
• Age ≥ 18 and ≤ 85.
• NIHSS score ≥ 8 and ≤ 25.
• Prestroke mRS score of ≤ 1.
• Intracranial arterial occlusion of the distal intracranial carotid artery or middle cerebral artery (M1/M2), anterior cerebral artery (ACA), posterior cerebral artery (PCA), basilar artery, or vertebral artery demonstrated with DSA.
• Thrombectomy procedure can be initiated within 8 hours from symptom onset (defined as time last known well [TLKW]) and at least one NeVa pass occurring within 8 hours.
• Imaging
  Inclusion Criteria:
  • Non-Contrast CT Selection (if CT Perfusion or MRI not utilized): ASPECTS 6-10 ; or
  • CT Perfusion core ≤ 50 cc; or
  • MRI DWI core ≤ 50 cc.
• Subject or legal representative is able and willing to give informed consent prior to the intervention

• Pre-existing medical neurological or psychiatric disease that would confound the neurological or functional evaluations; e.g., dementia with prescribed anti-cholinesterase inhibitor (e.g., Aricept).
• Cardiopulmonary resuscitation, cardiac arrhythmia resulting in hemodynamic instability (hypotension) that is not easily medically correctable, evidence of ongoing myocardial infarction, concern for pre-treatment pulmonary aspiration.
• Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
• Cerebral vasculitis.
• History of severe allergy to contrast medium.
• Known allergy to NeVa materials (nitinol, stainless steel).
• Suspicion of aortic dissection, septic embolus, or bacterial endocarditis.
• Systemic infection.
• Significant mass effect with midline shift.
• Evidence of intracranial tumor (except small meningioma [≤ 3 cm]).
• Any CT or MRI evidence of acute hemorrhage products on presentation.
• Inability to deploy NeVa device for at least one pass for any other reason.
• Life expectancy less than 6 months.
• Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed.
• Females you are pregnant or breastfeeding.
• Active malignancy.
• Stenosis or occlusion in a proximal vessel requiring treatment or preventing access to the thrombus.

• Age ≥ 65 years.
• Histologically confirmed newly diagnosed Grade IV malignant glioma.
• Planned radiation treatments at Mayo Clinic Arizona or Mayo Clinic Rochester.
• Willing to sign release of information for any radiation and/or follow-up records.
• Provide informed written consent.
• Patients with eGFR ≥ 60 mg/min/1.72m^2.
• Ability to complete questionnaire(s) by themselves or with assistance.
• ECOG performance status 0, 1, 2.

• Patients diagnosed with Grades I-III glioma.
• Currently on Avastin at time of treatment.
• Unable to undergo MRI scans with contrast (e.g., cardiac pacemaker, defibrillator, kidney failure).
• Unable to undergo an 18F-DOPA-PET scan (e.g., Parkinson’s Disease, taking anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from discontinuance of dopamine agonists).
  • NOTE: Other potentially interfering drugs: amoxapine, amphetamine, benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, paroxetine, citalopram, and sertraline. If a patient is on any of these drugs, list which ones on the On-Study form.
• Pregnant women, nursing women, or men or women of childbearing potential who are unwilling to employ adequate contraception.
  • NOTE: All women enrolled in this study will be age 65 or over, and at the determination of the PI, will not be of childbearing potential.  If the radiology department requires a pregnancy test before administering the 18FDOPA injection, they may perform one per their standard of care.

Eligibility last updated 7/1/22. Questions regarding updates should be directed to the study team contact.

• Treatment-naïve or relapsed/refractory CLL patients undergoing CLL antineoplastic treatment. Diagnosis of B-cell CLL established according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and documented within medical records.
• Hypogammaglobulinemia (IgG levels < 5 g/L) as confirmed by the Central Laboratory.
• ≥ 18 years of age.
• Voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted.

• IgG treatment within 3 months prior to Screening.
• Antibiotic prophylaxis and/or treatment within 7 days prior to Baseline (with the exception of trimethoprim-sulfamethoxazole [TMP/SMX], diaminodiphenyl sulfone [dapsone] and pentamidine inhalation).
• Current major infection or > 1 major infection in the previous 6 months before Baseline.
• History of anaphylaxis or severe systemic response to immunoglobulin, blood or plasma-derived products or any Panzyga component.
• History of a non-CLL malignancy or other medical condition with life-expectancy of less than two years.
• Severe liver disease, with signs of ascites and/or hepatic encephalopathy.
• Severe kidney disease (as defined by estimated glomerular filtration rate [eGFR] 140 kg.
• Eastern Cooperative Oncology Group (ECOG) performance score of > 2.
• Female patients of childbearing potential unwilling to use a protocol-required method of contraception from the Screening Visit throughout the study treatment period and for 30 days following the last dose of study drug.
• Human immunodeficiency virus (HIV) infection at Screening (defined for the study as positive HIV antibody test).
• Patients found to be chronic carriers of hepatitis B virus (HBV), defined by positive surface antigen (HBsAg), positive Hepatitis B core antibodies (HBcAb) and/or low HBV titers, who will not receive targeted antiviral therapy while undergoing CLL therapy, and patients with active HBV, defined as high HBV titers.
• Uncontrolled hepatitis C infection at Screening (defined for the study as positive hepatitis virus C [HCV] polymerase chain reaction [PCR]).
• Pregnant and lactating women.
• Subjects with a history of thromboembolic events (TEE) such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease (Fontaine IV) within 6 months before Baseline.
• Planned or ongoing immunosuppressive treatment (other than for CLL or corticosteroids) or other forbidden medication during the entire study duration after study enrollment.
• Participation in another interventional clinical trial that is either blinded or involves an investigational (not approved) product within 3 months before Baseline or during the course of the clinical study. Participation in observational clinical trials or open-label trials involving an approved product may be permitted after consultation with the medical monitor.

Eligibility last updated 3/18/22. Questions regarding updates should be directed to the study team contact.