Inclusion Criteria

• Female patient volunteers
• Ages 21 years and older
• No history of mastectomy or implants
• Identified to have findings on their clinical breast ultrasound
  • It is anticipated that the majority of these participants will undergo a standard of care biopsy 
  • Both the ultrasound and our proposed imaging method data collection from each participant will take place before the biopsy
• Also healthy female voluteers with no findings on their clinical breast ultrasound

Exclusion Criteria

• Previous mastectomy or implants
• Any condition that does not allow proper use of our imaging devices

• Documented type 2 diabetes for at least 3 months, or prediabetes. Those with type 2 diabetes must be prescribed a lifestyle intervention alone or in combination with a stable dose(s) of at least one glucose-lowering medication during the 8 weeks prior to the screening visit.
• Hemoglobin A1c inclusion criteria as follows: i. Hemoglobin A1c of 6-11% (inclusive) for patients with documented type 2 diabetes receiving metformin monotherapy; ii. Hemoglobin A1c of 6.5-11% (inclusive) for patients with documented type 2 diabetes receiving any type of glucose-lowering medication (except metformin monotherapy); iii. Hemoglobin A1c of 6.0-6.9% (inclusive) for patients with documented type 2 diabetes receiving lifestyle intervention alone; iv. Hemoglobin A1c of > 5.7% and < 6.5 % for patients with pre-diabetes
• Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
• Ejection fraction (EF) ≥ 45% as determined on imaging study within 18 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function
• Elevated NT-proBNP ≥ 300 pg/ml or BNP ≥ 100 pg/ml. For patients with permanent atrial fibrillation inclusion thresholds will be BNP ≥ 125 pg/mL or NTproBNP ≥ 500 pg/mL
• Stable medical therapy for heart failure for 30 days
• On a diuretic ≥30 days prior to screening visit and a stable diuretic therapy for 14 days
• At least one of the following:
  • i. Hospitalization for decompensated HF in the last 12 months;
  • ii. Acute treatment for HF with intravenous loop diuretic or hemofiltration in the last 12 months;
  • iii. Mean pulmonary capillary wedge pressure ≥15 mmHg or LV end diastolic pressure (LVEDP) ≥15 mmHg documented during catheterization at rest, or pulmonary capillary wedge pressure or LVEDP ≥25 mmHg documented during catheterization with exercise;
  • iv. Structural heart disease evidenced by at least one of the following echo findings (any local measurement made within the 18 months prior to screening visit):
    • 1) left atrial (LA) enlargement defined by at least one of the following: LA width ≥3.8cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55mL or LA volume index ≥29 mL/m2 2) OR left ventricular hypertrophy (LVH) defined by septal thickness or posterior wall thickness ≥1.1 cm.

• Decompensated heart failure (hospitalization for heart failure within the 30 days prior to screening)
• History of type 1 diabetes 
• History of diabetic ketoacidosis
• Hemoglobin A1c <5.7 or >11% at the screening visit
• Estimated glomerular filtration rate (eGFR) < 30 at the screening visit
• Admission for an acute coronary syndrome (ST-elevation MI, non-ST-elevation MI, or unstable angina), percutaneous coronary intervention, or cardiac surgery within 60 days prior to the screening visit.
• Admission for cardiac resynchronization therapy (CRT) within 90 days prior to the screening visit
• Planned cardiovascular revascularization (percutaneous intervention or surgical) or major cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular assist device, cardiac transplantation, or any other surgery requiring thoracotomy, or transcatheter aortic valve replacement) or CRT within the 90 days after the screening visit.
• Participation in any interventional clinical trial (with an investigational drug or device) that is not an observational registry within 30 days of the screening visit.
• History of hypersensitivity to dapagliflozin
• For women of child-bearing potential: Current or planned pregnancy or currently lactating.
• Life expectancy <1 year at the screening visit
• Patients who are volume depleted based upon physical examination at the time of the screening or randomization visit
• BNP <100 pg/mL and NTproBNP<300 pg/mL at the screening visit. For patients with permanent atrial fibrillation exclusion thresholds will be BNP<125 pg/mL and NTproBNP<500pg/mL.
• Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin) or having received treatment with any SGLT-2 inhibitor within the 12 weeks prior to the screening visit.
• Average supine systolic BP <100 mmHg at the screening or randomization visit
• Past or current history of bladder cancer
• Active Hematuria
• Donation of blood or bone marrow 12 weeks prior to the screening visit and no planned donations during the study period
• Heart failure due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valve disease, and HOCM (hypertrophic obstructive cardiomyopathy).
• Heart failure due to severe aortic or mitral regurgitation
• Severe COPD thought to contribute to dyspnea
• Isolated right heart failure due to pulmonary disease
• Active and significant ischemia thought to contribute to dyspnea
• Documentation of previous EF < 40% at any time
• Complex congenital heart disease
• Uncontrolled hypertension, defined as systolic blood pressure ≥200 mmHg during the screening visit
• Any other condition that in the judgment of the investigator would jeopardize the patient's participation in the study or that may interfere with the interpretation of study data or if the patient is considered unlikely to comply with study procedures, restrictions and requirements
• Bariatric surgery within the past 6 months or planned bariatric surgery within the study time course.
• CardioMems device implantation within previous 4 weeks or planned CardioMems implantation during study period
• For echo substudy only: history of poor echo windows as judged by the investigator
• For echo substudy only: patients with ventricular paced rhythm or left bundle branch block on the most recent clinically available 12-lead electrocardiogram.
• For echo substudy only: permanent atrial fibrillation

• Patients within the Mayo Clinic Study of Aging 
• Patients 21-50 years old, 51-70 years old, and 71 and older   
• Patients with dementia from the Mayo Clinic ADRC

• Patients with glaucoma or other optic neuropathies will be excluded

• Patient is ≥ 18 years of age.
• LVEF 35%-50%.
• NYHA class I-II.
• QRS duration of ≥ 120 ms.
• Left bundle branch block (LBBB).
• Patient is able to receive a transvenous pectoral CRT implant.
• Patient is able to sign informed consent.
• Two echocardiograms are required to confirm LVEF ≤ 50% (one echo must be within 12 months of enrollment).
• Patient is on optimal and stable medical therapy (ACE inhibitor or AT1 blocker, beta blocker, etc. over the last 6 months).

• Advanced comorbid conditions with life expectancy <1 year.
• Patient is < 18 of years of age.
• Patient has a CRT device.
• Female patients who is pregnant or not on a reliable form of birth control. Women of childbearing potential are required to have negative pregnancy test within the 7 days prior to device implant.
• Unwilling or unable to return for required follow-up visits.
• Patient decides study participation is cost-prohibited.

1. 1. 1. Participants will be eligible to participate provided they meet the following criteria:
         1. Adults age 55 years and older
         2. Fluent in English
         3. Able to give informed consent at baseline
         4. Access and the ability to use the internet
         5. Access to a computer either at home or wherever they have quiet, uninterrupted access to the internet
         6. Availability of an eligible study partner
      2. Study partners will be eligible to participate provided they meet the following criteria:
         1. Adults age 18 years and older
         2. Have regular and frequent interaction (in person or by telephone or online contact) with the participant
         3. Fluent in English
         4. Able to give informed consent
         5. Access and the ability to use the internet
         6. Access to a computer either at home or wherever they have quiet, uninterrupted access to the internet

1. 1. 1. Participants will be excluded from participation if any of the following are present:
         1. Unable to give consent and/or unable to consent online at baseline (determined by online screening questionnaire in the Brain Health Registry)
         2. Evidence or diagnosis of dementia – Clinical Dementia Rating (CDR) greater than 1 at baseline. Participants who transition to Dementia or become untestable while in the study will be asked to remain in the study and continue to be followed. 
         3. Evidence of acute or uncontrolled medical illness
         4. Recent history (< 6 months) of abuse or dependence of drugs and/or alcohol
      2. Participants completing the supervised portion of the study, will be excluded for any of the following:
         1. Opinion of the Investigator that the participant is otherwise unsuitable for study
      3. Additionally, at the study sites that are already collecting the CDR, the study staff will gather reasons for why participants choose to decline or are excluded from completing the eCDR, as well as track the number of participants who complete the CDR but are excluded from this study. This information will be de-identified and shared with collaborators.

• Participants between 18-30 years of age.
• Healthy individuals that have participated in a routine physical activity in the past 12 months. 

• Participants under the age of 18 or over the age of 30.

• All subjects will be over the age of 21.
• Must have symptoms suggestive of a neurodegenerative and/or related disorder;  i.e., patients must have one or more neurological symptom that is insidious in onset and has worsened over time in nature.

Exclusion Criteria:

• Subjects will be excluded if they have any concurrent illnesses that could account for all of their symptoms, such as traumatic brain injury, encephalitis, strokes or developmental syndromes.
• Women that are pregnant or post-partum and breast-feeding will be excluded.
• All women who can become pregnant must have a pregnancy test before the PET/CT scan.
• Subjects will be excluded if they have any of the following genetic conditions which can increase the chance of cancer:
  • Cowden disease;
  • Lynch syndrome;
  • Hypogammaglobulinemia;
  • Wiskott-Aldrich syndrome;
  • Down’s syndrome.
• Subjects will be excluded from undergoing the MRI if it is contraindicated (metal in head, cardiac pace maker, etc), if there is severe claustrophobia, if there are conditions that may confound brain imaging studies (e.g., structural abnormalities, including subdural hematoma, intracranial neoplasm or large cortical infarcts), or if they are medically unstable or are on medications that might affect brain structure or metabolism (e.g., chemotherapy).

• Age ≥ 18 and ≤ 45 years at the time of screening.
• Clinical diagnosis of type 1 diabetes.
• Currently using an insulin pump at the time of screening.
• HbA1c ≤ 9%, as performed by point of care or central laboratory testing. A1c will be assessed at the screening visit.
• Pregnant 140/7 to 326/7 weeks gestation.
• Singleton pregnancy without any other significant known complications, such as preeclampsia, premature rupture of membranes, 2nd/3rd trimester bleeding, fetal growth or fluid abnormalities.
• No proven or suspected fetal malformations diagnosed in the current pregnancy.
• Bolus for all meals and snacks that contain ≥ 5 grams of carbohydrate.
• Willing to switch to Novolog or Humalog, or continue Novolog or Humalog for the duration of closed-loop use.
• Willingness not to start any new non-insulin glucose-lowering agent during the course of the trial.
• Willing to abide by the study protocol and use study-provided devices.
• Have a care partner with the following responsibilities: knowing subject whereabouts and being promptly available for contact by study staff during the day and night, residing in the same dwelling as subject during the night, being agreeable to all device training during the supervised HCL session and additional training on hyper- and hypoglycemia treatment, and assisting with emergency care if needed, such as transportation to the hospital or emergency department.

• Known unstable cardiac disease or untreated cardiac disease, as revealed by history or physical examination.
• Concurrent use of Afrezza or any non-insulin glucose-lowering agent other than metformin (including GLP-1 agonists, Pramlintide, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas).
• Hemophilia or any other bleeding disorder.
• Prior history of Preterm Premature Rupture of Membranes (PPROM).
• Significant hyperemesis interfering with carbohydrate intake.
• Laboratory results:
  • A1C > 9%;
  • Abnormal liver or renal function (Transaminase > 2 times the upper limit of normal, creatinine > 1.5 mg/dL);
  • Liver and renal function testing drawn at screening visit or within three months prior to screening (for other purposes) will suffice for enrollment purposes,
• Dermatological conditions that would preclude wearing a CGM sensor or infusion site.
• Any condition that could interfere with participating in the trial, based on investigator judgment.
• Participation in another pharmaceutical or device trial at the time of enrollment or during the study.
• Having a direct supervisor at place of employment who is also directly involved in conducting the clinical trial (as a study investigator, coordinator, etc.); or having a first-degree relative who is directly involved in conducting the clinical trial.
• History of severe hypoglycemia in the past 6 months.
• History of DKA requiring hospitalization in the past 6 months.
• Significant chronic kidney disease (eGFR < 60) or hemodialysis.
• Significant liver disease.
• History of adrenal insufficiency.
• History of abnormal TSH consistent with hypothyroidism or hyperthyroidism that is not appropriately treated.
• History of high dose steroid use in the past 8 weeks.

• Patient must be 18 years of age or older, at the time of signing the informed consent.
• Anti-aquaporin-4 antibody-positive and a diagnosis of NMOSD as defined by the 2015 international consensus diagnostic criteria.
• At least 1 attack or relapse in the last 12 months prior to the Screening Period.
  • NOTE: Patients with a single life-time attack will be considered to satisfy inclusion criterion #3 if the attack occurred in the last 12 months.
• Expanded Disability Status Scale score ≤ 7.
• Patients who enter the trial receiving supportive IST (eg, corticosteroids, azathioprine [AZA], mycophenolate mofetil [MMF], methotrexate [MTX], and tacrolimus [TAC]) for the prevention of relapse, either in combination or monotherapy, must be on a stable dosing regimen of adequate duration prior to Screening with no plan to change the dose during the study period (defined as from the screening visit through the end of the study) as follows: a. If patients who enter the study are receiving AZA, they must have been on AZA for ≥ 6 months and have been on a stable dose for ≥ 2 months prior to Screening. b. If patients who enter the study are receiving other ISTs (eg, MMF, MTX, or TAC), they must have been on the IST for ≥ 3 months and have been on a stable dose for ≥ 4 weeks prior to Screening. c. If patients who enter the study are receiving oral corticosteroids, they must have been on a stable dose for ≥ 4 weeks prior to Screening. d. If a patient enters the trial receiving oral corticosteroid(s) with or without other IST(s), the daily corticosteroid dose must be no more than prednisone 20 mg/day (or equivalent) prior to Screening.
• Vaccinated against N. meningitidis within 3 years prior to, or at the time of, initiating ravulizumab. Patients who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination.
• Body weight ≥40 kilograms.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male patients must agree to use contraception as detailed in the protocol during the treatment period and for at least 8 months after last dose of study drug and refrain from donating sperm during this period;
  • Not a woman of childbearing potential (WOCBP) OR • Is a WOCBP and using a highly effective or acceptable contraceptive method as described in Section 10.4 during the treatment period and for a minimum of 8 months after the last dose of study drug. − The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study drug. A WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose of study drug. Additional requirements for pregnancy testing during and after study drug. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• 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.

• History of N. meningitidis infection.
• Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer).
• History of unexplained infections.
• Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug administration on Day 1.
• Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on Day 1.
• Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
• Any medical condition that, in the opinion of the Investigator, might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient.
• Previously or currently treated with a complement inhibitor.
• Use of rituximab within 3 months prior to Screening.
• Use of mitoxantrone within 3 months prior to Screening.
• Use of Intravenous Immunoglobulin (IVIg) within 3 weeks prior to Screening.
• Participation in any other investigational drug study or exposure to an investigational drug or device within 30 days of Screening or 5 half-lives of the investigational drug, whichever is greater.
• Pregnant, breastfeeding, or intending to conceive during the course of the study.
• Patient is currently treated with a biologic medication that may affect immune system functioning, or has stopped treatment with a biologic medication that may affect immune system functioning, and 5 half-lives of the medication have not elapsed by the time of the Screening visit, unless otherwise specified in the protocol.
• Participation in the PREVENT study (ECU-NMO-301), regardless of the study drug received (eculizumab or placebo).

• Patients age ≥ 10 to < 22 with the diagnosis of adolescent idiopathic scoliosis being seen for scoliosis treatment (any skeletal maturity level, Risser 0-5).
• Curves > 35 degrees, < 70 degrees,
• Patient has consulted with a spine specialist regarding surgery of treatment of their scoliosis and surgery (fusion or non-fusion) has been considered, or the patient has undergone surgery for treatment of their scoliosis within the past three years.
• English speaking with parent/guardian present and willing to participate.
• Male and females.
• Patients < 3 years postop fusion and/or tether.

• None.

• Patients age ≥ 10 to < 22 with the diagnosis of adolescent idiopathic scoliosis being seen for scoliosis treatment (any skeletal maturity level, Risser 0-5).
• Curves > 35 degrees, < 70 degrees,
• Patient has consulted with a spine specialist regarding surgery of treatment of their scoliosis and surgery (fusion or non-fusion) has been considered, or the patient has undergone surgery for treatment of their scoliosis within the past three years.
• English speaking with parent/guardian present and willing to participate.
• Male and females.
• Patients < 3 years postop fusion and/or tether.

• None.

• Adult subjects of all ages, both sexes and all races will be included in this study.
• Subjects must be 18 years of age or older.
• Subjects with HCC are eligible for this trial. HCC is defined as having at least one of the following:
  • Biopsy proven HCC or:
    • A discrete hepatic tumor(s) as defined by the Barcelona (29) criteria for cirrhotic subjects;
    • ≥ 2cm with arterial hypervascularity and venous or delayed phase washout on CT or MRI.
• Subjects are liver transplant candidates (actively awaiting organ transplant per transplant services in documentation), or, potential liver transplant candidates (at the discretion of the liver team and/or Principal Investigator) advised by liver transplant services as needing local treatment prior to liver transplant evaluation.
• Subjects must be within UCSF criteria (one solitary tumor smaller than 6.5 cm, or patients having 3 or fewer nodules, with the largest lesion being smaller than 4.5 cm or having a total tumor diameter less than 8.5 cm without vascular invasion) and eligible for potential liver transplant.
• Subjects must be eligible per standard of care for either TACE or SBRT procedures.
• Subjects must have a life expectancy of at least 12 weeks.
• Subjects must sign an informed consent form approved for this purpose by the Institutional Review Board (IRB) of record .
• Subjects must have a Child-Turcotte-Pugh (CTP) score ≤ 8.
• Patients must have adequate organ function within 2 weeks of enrollment.
  • Bone marrow:
    • Platelets ≥ 30,000/mm^3.
  • Renal:
    • BUN ≤ 40 mg/dl; creatinine ≤ 2.0 mg/dl .
  • Hepatic:
    • INR ≤ 1.5 or correctable by Vitamin K, unless anti-coagulated for another medical reason.
  • Bilirubin < 3.0 mg/dl (in the absence of obstruction or pre-existing disease of the biliary tract; e.g., primary sclerosing cholangitis).
• Patients uninvolved liver volume will be estimated and must be > 700ml.
• Patients must have a Zubrod performance status of ≤ 2.
• Patients who are sexually active must agree to the use of contraception throughout the duration of the study.

• Bone marrow: Platelets ≥ 30,000/mm^3
• Renal: BUN ≤ 40 mg/dl; creatinine ≤  mg/dl
• Hepatic: INR ≤ 1.5 or correctable by Vitamin K, unless anti-coagulated for another medical reason.
• Bilirubin < 3.0 mg/dl (in the absence of obstruction or pre-existing disease of the biliary tract; e.g., primary sclerosing cholangitis).
• Patients’ uninvolved liver volume will be estimated and must be > 700ml.
• Patients must have a Zubrod performance status of ≤ 2.
• Patients who are sexually active must agree to the use of contraception throughout the duration of the study.

• Subjects in a “special category” as designated by FDA and the Canadian Institutes of Health or Canadian Panel on Research Ethics including subjects younger than 18, pregnant women, and prisoners.
• Refractory ascites that requires paracentesis for management.
• Known allergy to intravenous iodinated contrast agents unresponsive to prednisone pre-treatment.
• History of prior radiation to the liver.
• Evidence of metastatic disease.
• Presence of a Trans-jugular intra-hepatic porto-systemic shunt (TIPS).
• Untreated varices at high risk of bleeding.
• Bile duct occlusion or a prior diagnosis of an incompetent papilla.
• Acute infection.
• Uncorrectable bleeding disorder.
• Leukopenia, ANC < 1000/ul.
• Hepatic encephalopathy.
• Portal vein thrombosis.

• Confirmed diagnosis of NPC (NPC1 or NPC2) and at least one neurological symptom.
• The patient is two years of age or above.
• The patient is a permanent resident of US. -If taking miglustat (Zavesca®), the patient must have been on the target dose for the past six weeks.
• If the patient is sexually active, it is agreed to use effective contraception.
• Confirmed negative urine pregnancy test for sexually active female of child-bearing potential (post-menarche).
• If the patient has a history of seizures, the condition must be adequately controlled; i.e., the pattern of seizure activity must be stable, and the patient must be on a stable dose and regimen of antiepileptic medication during one month prior to screening.
• Patient or parent/guardian must provide written informed consent to participate in EAP.

• Severe liver insufficiency.
• Renal insufficiency.
• Known or suspected allergy or intolerance to arimoclomol or its constituents.
• The patient is pregnant, planning to become pregnant (while on the study) or is currently breastfeeding.
• The patient will undergo treatment with another investigational drug, whilst participating in the program or in the 4 weeks prior to commencing treatment with arimoclomol.
• The patient is either eligible and able to participate in or is currently participating in an active interventional clinical trial within the indication. The patient, in the opinion of the clinician, is unable to comply with the treatment or has a medical condition that would potentially increase the risk to the patient by participation.
• The patient has a medical condition which hinders the clinician's assessment of arimoclomol safety and efficacy (e.g., certain epileptic conditions or severe cataplexy).

• Female patients ≥ 18 years of age.
• Patients must have a confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
• Patients must have platinum-resistant disease:
  • Patients who have only had 1 line of platinum based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date last dose of platinum;
  • Patients who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum.
  • Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
  • Note: Patients who are platinum-refractory during front-line treatment are excluded (see exclusion criteria).
• Patients must have progressed radiographically on or after their most recent line of therapy.
• Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low risk, medically routine procedure for immunohistochemistry (IHC) confirmation of FRα positivity.
• Patient’s tumor must be positive for FRα expression as defined by the Ventana FOLR1 (FOLR-2.1) CDx assay.
• Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator).
• Patients must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment:
  • Adjuvant ± neoadjuvant considered one line of therapy
  • Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (i.e., not counted independently);
  • Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (i.e., not counted independently);
  • Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
• Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
• Time from prior therapy:
  • Systemic antineoplastic therapy (5 half-lives or 4 weeks, whichever is shorter);
  • Focal radiation completed at least 2 weeks prior to first dose of study drug.
• Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities.
• Major surgery must be completed at least 4 weeks prior to first dose and have recovered or stabilized from the side effects of prior surgery
• Patients must have adequate hematologic, liver, and kidney functions defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L (1,500/μL) without G-CSF in the prior 10 days or long-acting WBC growth factors in the prior 20 days;
  • Platelet count ≥ 100 x 10^9 /L (100,000/μL) without platelet transfusion in the prior 10 days;
  • Hemoglobin ≥ 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 21 days;
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN f. Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN);
  • Serum albumin ≥ 2 g/dL.
• Patients or their legally authorized representative must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
• Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) in while on study drug and for at least 3 months after the last dose of MIRV or at least 6 months after the last dose of Pac, PLD, or Topo.
• WCBP must have a negative pregnancy test within 4 days prior to the first dose of study drug.

• Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade or borderline ovarian tumor.
• Patients with primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first line platinum-containing chemotherapy.
• Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow.
• Patients with > Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE).
• Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision.
• Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
  • Active hepatitis B or C infection (whether or not on active antiviral therapy);
  • HIV infection;
  • Active cytomegalovirus infection;
  • Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before starting study drug.
  • Note: Testing at screening is not required for the above infections unless clinically indicated.
• Patients with history of multiple sclerosis or other demyelinating disease and/or LambertEaton syndrome (paraneoplastic syndrome).
• Patients with clinically significant cardiac disease including, but not limited to, any one of the following:
  • Myocardial infarction ≤ 6 months prior to first dose;
  • Unstable angina pectoris;
  • Uncontrolled congestive heart failure (New York Heart Association > class II);
  • Uncontrolled ≥ Grade 3 hypertension (per CTCAE);
  • Uncontrolled cardiac arrhythmias.
• Patients assigned to PLD stratum only:
  • Left ventricular ejection fraction (LVEF) below the institutional limit of normal as measured by echocardiography (ECHO) or multigated acquisition (MUGA) scan.
• Patients with a history of hemorrhagic or ischemic stroke within six months prior to randomization.
• Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C).
• Patients with a previous clinical diagnosis of non-infectious interstitial lung disease (ILD), including noninfectious pneumonitis.
• Patients with required use of folate-containing supplements (e.g., folate deficiency).
• Patients with prior hypersensitivity to monoclonal antibodies.
• Women who are pregnant or lactating.
• Patients with prior treatment with MIRV or other FRα-targeting agents.
• Patients with untreated or symptomatic central nervous system (CNS) metastases.
• Patients with a history of other malignancy within 3 years prior to randomization.
  • Note: does not include tumors with a negligible risk for metastasis or death (e.g., adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast).
• Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
• People who are detained through a court or administrative decision, receiving psychiatric care against their will, adults who are the subject of a legal protection order (under tutorship/curatorship), people who are unable to express their consent, and people who are subject to a legal guardianship order.
• Simultaneous participation in another research study, in countries or localities where this is the health authority guidance.

• Males or females.
• Patients with the of NET who are planned and eligible to receive PRRT will be considered for enrollment.
• Patients must be > 18 years-old and able to consent.

• Any patients who does not meet the above criteria, declines participation in research activity, or has hemoglobin is < 8 gm/dl at baseline. 

• Patient must be willing and able to provide written informed consent prior to any clinical investigation-related procedure.
• Age ≥ 18 years.
• Patient has chronic (at least 6 months), refractory axial low back pain with a neuropathic component and is not a candidate for spine surgery.
• Patient has back pain for ≥ 6 months inadequately responsive to supervised conservative care.
• Patient has not had spine surgery for back or leg pain.
• Patient is a candidate for spinal cord stimulation.
• Low back pain ≥ 6 on Numerical Rating Scale.
• Oswestry Disability Index score of ≥ 30%.
• Willing and able to comply with the instructions for use, operate the study device, and comply with this Clinical Investigation Plan.

• Pathology seen on imaging tests obtained within the past 12 months that is clearly identified and is likely the cause of the CLBP, that can be addressed with surgery.
• Primary complaint of leg pain, or leg pain is greater than back pain.
• Back pain is due to any of the following:
  • spinal instability defined as > 2 mm translation on radiographic imaging;
  • visceral causes (e.g., endometriosis or fibroids);
  • vascular causes (e.g., aortic aneurysm);
  • spinal infection (e.g., osteomyelitis);
  • inflammation or damage to the spinal cord (e.g., arachnoiditis or syringomyelia);
  • tumor or spinal metastases.
• Has widespread pain (e.g., fibromyalgia) or pain in other area(s), not intended to be treated in this study (e.g., neck pain, shoulder pain).
• Patient has seronegative spondyloarthropathy (e.g., rheumatoid, lupus, psoriatic).
• Neurological deficit (e.g., foot drop).
• Prior lumbar spine surgery or sacroiliac joint fusion.
• Patient has used a morphine equivalent daily dose of more than 50 MEQ at any time in the last 90 days (3 months).
• Patient is bed bound.
• Patients with regular intake of systemic steroids (except inhaled steroids used to treat asthma).
• Imaging (MRI, CT, X-ray) findings within the last 12 months that contraindicates lead placement.
• Known allergic reaction to implanted materials.
• Severe scoliotic deformity (> 11 degrees in thoracic or lumbar spine).
• Patient has a history of, or existing intrathecal drug pump.
• Patient has previous experience with neuromodulation devices, including a failed trial.
• BMI > 40.
• Patient is enrolled, or intends to participate, in another clinical drug and/or device study or registry that may interfere with the results of this study, as determined by Abbott personnel.
• 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 of the clinical investigation results.
• Failed psychological evaluation.
• Evidence of untreated mental illness, or substance abuse.
• Patient demonstrated 2 or more Waddell’s signs of inorganic behavior.
• Patient is in current litigation for back pain/injury, or is currently receiving worker’s compensation.
• Pregnant or nursing subjects and those who plan pregnancy during the clinical investigation follow-up period.
  • Female subjects of child-bearing potential must have a negative pregnancy test done within 7 days prior to enrollment/baseline visit per site standard test.

• Adults, ≥ 18 years old.

• Children under 18 years of age.
• Adults lacking capacity to consent.
• Adults with impaired decision making.

• Provide written, informed consent to participate in the study and follow the study procedures. The Investigator takes responsibility for ensuring that all vulnerable patients are protected and participate voluntarily in an environment free from coercion or undue influence.
• Male or female patients ≥ 12 years of age at the time of signing the informed consent form (ICF), except where local regulations, countries, and/or institutional policies do not allow for patients < 18 years of age (adolescents) to participate. In regions where adolescents are not allowed to participate in the study due to age restrictions, enrolled patients must be ≥ 18 years of age.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (≥ 17 years of age)/Lansky Performance Score ≥ 80% (12 to 16 years of age, inclusive).
• Histologically confirmed Stage IIIA (LN metastasis > 1 mm [i.e., at least one LN metastasis measuring > 1 mm at greatest diameter]), IIIB/C/D, or IV (M1a/b/c/d) cutaneous melanoma by AJCC (8th edition) at study entry:
  • Patient must be completely surgically resected within 12 weeks prior to randomization;
  • Patients with in-transit or microsatellite disease will be allowed if disease has been completely surgically resected;
  • Patients must have been surgically rendered free of disease with negative surgical margins documented, as applicable.
• Prior treated central nervous system (CNS) metastases must have magnetic resonance imaging (MRI) evidence of no recurrence for at least 4 weeks after treatment, subjects must be off immunosuppressive doses of systemic steroids (> 10 mg/day or equivalent) for at least 14 days prior to study drug administration and must have returned to neurologic baseline post-operatively. (The 4-week period of stability is measured after the completion of the neurologic interventions [i.e., surgery and/or radiation]).
  • Note: Leptomeningeal disease is excluded.
• In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 14 days before study drug administration.
• Tumor tissue available from biopsy or resected disease must be provided to central laboratory for biomarker and PD-L1 status analysis. Must have PD-L1 expression classification (≥ 1%, < 1%, indeterminate, or not evaluable) prior to randomization.
• Disease-free status documented by a complete physical examination and imaging studies within 28 days prior to randomization.
• Demonstrated adequate organ function, as defined below:
  • White blood cells ≥ 2000/μL;
  • Absolute neutrophil count ≥ 1500/μL (1.5 × 109 /L);
  • Hemoglobin ≥ 9.0 g/dL (90 g/L);
  • Platelet count ≥ 100 × 109 /L;
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (except patients with Gilbert Syndrome, who must have total bilirubin < 3.0 mg/dL);
  • Alanine aminotransferase (ALT) ≤ 3 × ULN;
  • Aspartate aminotransferase (AST) ≤ 3 × ULN;
  • Serum creatinine ≤ 1.5 × ULN (133 μmol/L) OR calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula and actual body weight).
• A documented left ventricular ejection fraction (LVEF) > 45% using standard echocardiogram or multigated acquisition (MUGA) scan test.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 14 days prior to the start of study treatment.
• Women must not be breastfeeding.
• WOCBP must agree to follow instructions for methods of contraception for the duration of treatment with study treatment and for 5 months after bempegaldesleukin and/or nivolumab treatment completion. WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this protocol.
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with bempegaldesleukin and 3 months after bempegaldesleukin treatment completion. In addition, male patients must be willing to refrain from sperm donation during this time.
• Patients must be able and willing to comply with the study visit schedule and study procedures.

• Use of an investigational agent or an investigational device within 28 days before randomization.
• Female patients who are pregnant or lactating, who plan to get pregnant, or who have a positive serum or urine pregnancy test.
• History of ocular/uveal melanoma or mucosal melanoma.
• Active, known or suspected autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 30 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Prior therapy for melanoma.
  • Exceptions include surgery for the melanoma lesion(s) and/or adjuvant radiation therapy for CNS lesions at least 28 days prior to randomization. Patients must have recovered from all Grade ≥ 2 radiation-related toxicities.
• Prior therapy with interferon, talimogene laherparepvec (Imlygic®), IL-2 directed therapy, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways).
• History of leptomeningeal disease.
• History of hypersensitivity or allergy to study drug components (for nivolumab, bempegaldesleukin, or any of their excipients).
• History of severe hypersensitivity reaction to any monoclonal antibody.
• Prior malignancy active within the previous 3 years except for locally potentially curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Consult with the Medical Monitor about prior melanoma or other potential exceptions.
• History of allogeneic stem cell transplant; history of solid organ or tissue transplant that requires systemic use of immune suppressive agents.
• Prior surgery that required general anesthesia within 28 days before the first dose of study treatment; surgery requiring local/epidural anesthesia within 72 hours before first dose.
• Active infection requiring systemic therapy within 14 days prior to randomization.
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on Screening chest computed tomography (CT) scan.
• Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus (e.g., hepatitis B surface antigen [HBsAg, Australia antigen] positive, or hepatitis C antibody [anti-HCV] positive [except if HCV-RNA negative]).
• Any positive test result for immunodeficiency or active human immunodeficiency virus (HIV-1/2 antibodies).
• Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening.
• Unstable or deteriorating cardiovascular disease within the previous 12 months prior to Screening including, but not limited to, the following:
  • Unstable angina or myocardial infarction;
  • Congestive heart failure (New York Heart Association Class III or IV);
  • Uncontrolled clinically significant arrhythmias.
• Transient ischemic attack (TIA) or CVA within 12 months prior to Screening.
• Need for > 2 antihypertensive medications for management of hypertension (including diuretics). Patients with hypertension must be on a stable antihypertensive regimen for the 14 days prior to randomization.
  • Note: An antihypertensive medication that contains 2 drugs under one formulation is counted as 2 antihypertensive medications (e.g., angiotensin-converting-enzyme [ACE] inhibitor plus diuretic, calcium channel blocker plus ACE inhibitor).
• History of pulmonary embolism, deep vein thrombosis, or prior clinically significant venous or non-CVA/TIA arterial thromboembolic event (e.g., internal jugular vein thrombosis) within 3 months prior to randomization. Note: Patients with a history of a venous or arterial thromboembolic event must be asymptomatic for at least 2 weeks prior to randomization and must be receiving a stable regimen of therapeutic anticoagulation (preferably low molecular weight heparin [LMWH] or direct oral anticoagulation [DOAC].
  • Note: Unless there is a new medical contraindication observed after Cycle 1 Day 1, a patient with a history of venous or arterial thromboembolic event must be maintained on therapeutic anticoagulation throughout participation on the treatment phase of the study.
• Patients with inadequately treated adrenal insufficiency.
• Patients who have received a live/attenuated vaccine within 30 days of randomization.
• Known current drug or alcohol abuse.
• Receiving any medication prohibited in combination with study treatments as described in the respective product labels, unless medication was stopped within 7 days prior to randomization.
• Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results (e.g., a condition associated with diarrhea or acute diverticulitis).

Eligibility last updated 9/9/21.  Questions regarding updates should be directed to the study team contact.

• Is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• Must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Is willing and able to adhere to the study visit schedule and other protocol requirements.
• Consents to retrieve formalin-fixed paraffin-embedded (FFPE) archival tumor tissue, either in tumor blocks or sectioned/mounted specimens, if collected within the last year and if using in place of biopsy at screening.
• Has histologically confirmed (per local evaluation) diagnosis of lymphoma according to 2016 WHO classification including:
  • Cohort A and Cohort D: all subtypes including B-cell, T-cell and NK-cell NHL, and cHL;
  • Cohort B: all B-cell NHL;
  • Cohort E: aggressive B-cell lymphoma including DLBCL NOS, high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements, Grade 3b FL and PMBCL;
  • Cohorts C, F and G: FL Grade 1 to 3a and MZL including extranodal marginal zone lymphoma (ENMZL) of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma (NMZL) and splenic marginal zone lymphoma (SMZL).
• Relapsed or refractory disease according to the following definitions:
  • Aggressive B-cell lymphoma: after at least 2 prior lines of therapy including R-CHOP-like regimen;
  • FL and MZL: following at least 2 prior lines of systemic therapy (being previously exposed to at least 1 anti-CD20 mAb and 1 alkylating agent) and in need for treatment; local involved field radiotherapy for limited stage disease is not considered as a previous line.
  • Note: for SMZL, splenectomy is considered as 1 line; for ENMZL, Helicobacter pylori eradication is not considered as a previous line.
  • MCL: following at least 2 prior lines of therapy including at least 1 immunochemotherapy and 1 BTK inhibitor;
  • PTCL: following at least 2 prior lines of therapy OR after 1 prior line of standard therapy and being not eligible for any other approved regimen;
  • cHL: following at least 2 prior systemic lines of therapy and previously exposed to brentuximab vedotin and anti-PD1;
  • All other subtypes: following at least 2 prior lines of therapy;
  • Subjects previously treated with CAR-T therapy can be enrolled (irrespective of the indication).
• Subjects must not be eligible for any other approved treatment for their underlying lymphoma as assessed by the Investigator.
• Must have measurable disease defined by at least 1 fluorodeoxyglucose (FDG)-avid lesion for FDG-avid subtype and 1 bi-dimensionally measurable (> 1.5 cm in longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI), as defined by the Lugano classification (Cheson, 2014). Site of measurable disease cannot be previously irradiated.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Must have the following laboratory values:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L or ≥ 1.0 x 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without growth factor support for 7 days (14 days if pegfilgrastim);
  • Hemoglobin (Hb) ≥ 8 g/dL;
  • Platelets (Plt) ≥ 75 x 10^9 /L or ≥ 50 x 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without transfusion for 7 days;
  • Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 2.5 x ULN;
  • Serum total bilirubin ≤ 1.5 ULN except in cases of Gilbert’s syndrome, then ≤ 3.0 ULN;
  • Estimated serum creatinine clearance of ≥ 50 mL/min using the modification of diet in renal disease formula or directly determined from the 24-hour urine collection method.
• All subjects must:
  • Have an understanding that the study drug could have a potential teratogenic risk;
  • Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment;
  • Agree not to share study medication with another person;
  • Agree to follow all requirements defined in the Pregnancy Prevention Program for CC-220 Pregnancy Prevention Plan for Subjects in Clinical Trials.
• Females must agree to abstain from breastfeeding during study participation and for at least 28 days after CC-220 discontinuation and according to the approved rituximab or obinutuzumab product/prescribing information.
• Females of childbearing potential (FCBP*) must:
  • Have 2 negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence** from heterosexual contact;
  • Either commit to true abstinence** from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting investigational product, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of CC-220, for 12 months after the last dose of rituximab or 18 months following the last dose of obinutuzumab, whichever is longer.
• Male subjects must:
  • Practice true abstinence2 (which must be reviewed on a monthly basis and source documented) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 90 days after the last dose of CC-220, rituximab or obinutuzumab, whichever is longer, even if he has undergone a successful vasectomy;
  • Must agree to refrain from donating sperm while on study treatment, during dose interruptions and for at least 90 days following last dose of CC-220, rituximab or obinutuzumab, whichever is longer.
• *A FCBP is a female who:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• ** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

• Any significant medical condition, active infection (including severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] suspected or confirmed), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Any condition that confounds the ability to interpret data from the study.
• Life expectancy ≤ 3 months.
• Diagnosis of lymphoblastic lymphoma.

Eligibility last updated 8/12/21. Questions regarding updates should be directed to the study team contact.

• Adults, ≥ 18 years of age.
• For rheumatoid arthritis patients:
  • 2010 EULAR/ACR classification criteria of RA.
• For cancer patients on ICI therapy without irAEs, they will be matched to our existing IA-irAE patients by age, sex, cancer types and ICI treatment.

• < 18 years of age.
• For rheumatoid arthritis cohort:
  • Active infection;
  • Pregnancy;
  • Any cancer diagnosis;
  • Treatment with biologics;
  • Active use of high dose (≥ 30 mg daily) of prednisone or steroid equivalent;
  • Clinical features suggestive of other non-RA rheumatic disease (e.g., psoriatic arthritis, reactive arthritis, ankylosing spondylitis, lupus, Sjogren’s, , etc) or axial spondyloarthropathy.
• For cancer patient control cohort:
  • No irAE ≤ 6 months following final ICI treatment.

Inclusion Criteria
•Controls:

• Healthy volunteers
   aged 18-80 years old
• Able to provide written informed consent before participating in the study.
• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Inclusion Criteria
•Constipated Patients:

• Male and female volunteers aged 18-80 years.
• Individuals with chronic constipation for 1 year, with 2 or more of the following symptoms for 3 months or longer: < 3 bowel motions/week, straining ≥ 25% of time, hard or lumpy stools ≥ 25% of time, anal digitation ≥ 25% of time, incomplete evacuation ≥ 25% of time, feeling of anorectal blockage ≥ 25% of time.
• Able to provide written informed consent before participating in the study.
• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Exclusion Criteria
•Controls:

Items marked with an asterisk also apply to patients

• Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study and/or pose safety concerns.*
• Current symptoms of a functional gastrointestinal disorder assessed by questionnaire.
• Putative risk factors for pelvic floor trauma; i.e., six or more vaginal deliveries, birthweight > 4500gms (macrosomia), or known 3rd or 4th degree perineal tear.
• Medications that are likely to alter gastrointestinal motility: e.g., opiates and  anticholinergic medications; a stable dose of thyroxine and low doses of tricyclic agents (e.g., up to amitriptyline (50 mg daily).
• Active rectal inflammation, cancer; perianal sepsis; history of pelvic radiation in the past 3 years, rectal resection, or inflammatory bowel disease.*
• Anxiety or depression as assessed by the Hospital Anxiety and Depression Questionnaire.
• Pregnant women, prisoners and institutionalized individuals.*
• Patients with safety contraindications to routine clinical 7T MRI as determined by the Mayo Clinic Rochester MR Safety Committee.*
• Claustrophobic patients that cannot undergo MRI without anxiolytic medication.*
• Patients with known vestibular dysfunction.*     

Additional General Exclusion Criteria for 7T task fMRI:

All subjects and controls will be excluded from undergoing the task fMRI scan if they have:

• Active implant devices such as cardiac defibrillators/pacemakers, heart monitors, cohlear implants.
• Abandoned cardiac pacer wires.
• Orthopedic implants that are near the spinal cord or temperature sensitive organs.
• Metallic implants near the orbits.
• External devices that cannot be removed from the body (such as medicinal patches, piercings, jewelry, clothing or hair accessories).
• Temporary tattoos or those obtained prior to 1995.
• Colored contact lens.
• Any ‘undefined’ metallic implants of foreign bodies inside the patient.
• Are pregnant.

The following Inclusion criteria will apply to the patients with unilateral DRUJ instability.  In the symptomatic wrist, they will have:

• Point tenderness over the fovea, and one or more of the following:
  • instability of the DRUJ when compared to the uninjured side;
  • pain during pronation-supination over the DRUJ;
  • suspected pathology on previous fluoroscopy or MRI.
• In the contralateral wrist, an absence of DRUJ instability symptoms on physical exam.
• Individuals ≥ 15 years of age.

• Inability to be appropriately positioned in the scanner for the imaging.
• Diagnosed wrist osteoarthritis.
• Age under 15.

Eligibility last updated 8/26/22. Questions regarding updates should be directed to the study team contact.

• Male or female patients, ≥ 18 years.
• Patients with the ability to understand and give written informed consent for participation in this study including all evaluations and procedures as specified by this protocol.
• Patients agreeing to, and considered an acceptable and safe candidate for mandatory tumor tissue biopsy at screening and at the EoC1, with optional tumor biopsy at the time of disease progression.
  • Note: For baseline tissue samples, a specimen obtained up to 6 weeks prior to initiation of treatment on C1D1 and with no additional anticancer treatment given since biopsy collection.
• Patients with:
  • Sub-study 1 and Sub-study 2: Histologically diagnosed unresectable, locally advanced or metastatic BTC including adenocarcinoma of the intra- and/or extra-hepatic bile ducts and GBC. Patients with ampullary cancers are excluded.
  • Sub-study 3: Histologically diagnosed unresectable, locally advanced or metastatic ESCC.
• Patients must only have:
  • Sub-study 1 and Sub-study 2: Received and progressed on, or intolerant of, first-line gemcitabine and platinum-based chemotherapy in the metastatic/ advanced setting and should not have received prior anti-PD-(L)1 therapy. Patients with known fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement, or isocitrate dehydrogenase 1 (IDH1) mutation will be excluded. Prior anti-PD-(L)1 therapy may be allowed during the trial if regulatory approval for such therapy is obtained while this trial is enrolling.
  • Sub-study 3: Received and progressed on, or intolerant of, first-line platinum-based chemotherapy in the metastatic/advanced setting and should have received prior anti-PD- (L)1 therapy. Patients must have a best response of CR/PR or durable SD (defined as ≥ 3 months duration of SD) on prior anti-PD-(L)1 therapy. Patients with mixed adenosquamous histology cancers are excluded.
• Patients with measurable disease according to RECIST v1.1. 
• Patients with an ECOG PS of 0 or 1, and anticipated life expectancy of ≥ 3 months.
• Patients must have adequate organ function as indicated by the following laboratory values:
• Hematological
  • Absolute neutrophil count (ANC) ≥ 1,500/µL;
  • Platelets ≥ 75,000/µL;
  • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L*.
• Renal
  • Serum creatinine or measured or calculated creatinine clearance (CrCL)** ≤ 1.5 × upper limit of normal (ULN) or CrCL ≥ 30 mL/min for patients with a creatinine level of > 1.5 × ULN;
• Hepatic
  • Serum total bilirubin and direct bilirubin ≤ 1.5 × ULN;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for patients with liver metastases;
• Coagulation
  • International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT)  ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants***.  

*Criteria must be met without a transfusion within 2 weeks of the blood draw for screening.
**Glomerular filtration rate (GFR) can be used instead of serum creatinine or CrCL.
***Any patient receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study. Patients receiving a factor Xa inhibitor who have abnormal PT/ partial thromboplastin time (PTT) may be eligible after discussion with the Sponsor’s Medical Monitor.

• Women of childbearing potential agreeing to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 6 months after the last study drug dose.
• Male patients agreeing to use an adequate method of contraception starting with the first dose of study drug through 6 months after the last dose of study drug and to refrain from sperm donation during this period.

• Women who are pregnant or intending to become pregnant before, during, or within 6 months after the last dose of study drug; women who are breastfeeding; women of childbearing potential not using and not willing to use a highly effective method of contraception).
• Patients with central nervous system (CNS) malignancies; patients with known, untreated CNS or leptomeningeal metastases, or spinal cord compression, patients with any of the above not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.
• Note: Patients with treated CNS metastases will be eligible if they:
  • had radiotherapy, surgery or stereotactic surgery for the brain or spinal metastases;
  • have no neurological symptoms (excluding Grade ≤ 2 neuropathy);
  • have stable brain or spinal disease on the Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan within 4 weeks before signing the informed consent form (ICF);
  • must not be undergoing acute corticosteroid therapy or steroid taper. Chronic steroid therapy is acceptable provided that the dose is stable for the last 14 days prior to screening (≤ 10 mg prednisone daily or equivalent).
  • Spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.
  • Patients with known or suspected CNS metastases will require baseline imaging to establish stability of known lesion(s), or to assess for appearance of new brain lesion(s) or progression of existing lesion(s). MRI imaging is preferred for assessment of CNS lesions.
• Patients with significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, or unstable angina.
  • Note: Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• Patients with:
  • Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to the first study drug dose, unless adequately treated and considered by the Investigator to be stable;
  • Active uncontrolled bleeding or a known bleeding diathesis.
• Patients with a significant pulmonary disease or condition, including:
  • History of interstitial lung disease, pulmonary fibrosis;
  • History of pulmonary inflammatory disease, interstitial or other pneumonitis*, acute respiratory distress syndrome (ARDS).
  • * Patients with prior evidence of Grade 1 pneumonitis will be eligible provided they were asymptomatic when diagnosed and did not require treatment and provided pneumonitis has resolved prior to entry to this study.
• Patients with a current or recent (within 6 months) significant gastrointestinal disease or condition, including:
  • History of inflammatory bowel disease;
  • Diarrhea ≥ Grade 2 within 2 weeks prior to the first study drug dose.
• Gilbert’s syndrome or patients with UGT1A1*28 homozygosity (also known as UGT1A1 7/7 genotype).
• Patients with a significant ocular disease or condition, including history of an autoimmune or inflammatory disorder; e.g., episcleritis, uveitis, iritis.
  • Note: Patients with a history of dry eye for reasons other than an autoimmune disease or condition may be included if adequately treated. Patients with non-significant, non-inflammatory disorders (e.g., cataracts, glaucoma) will be allowed.
• Patients with an active, known or suspected autoimmune disease, or a documented history of autoimmune disease or syndrome, requiring systemic steroids or other immunosuppressive medications).
  • Note: Exceptions are permitted for type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, psoriasis or alopecia not requiring systemic treatment, conditions not expected to recur in the absence of an external trigger.
• Patients with a history of organ transplantation (e.g., stem cell or solid organ transplant).
• Patients with human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active infection with hepatitis B virus (HBV) (e.g., HBsAg reactive) or hepatitis C virus (HCV) (e.g., HCV RNA [qualitative] is detected). (Inactive HBsAg carriers with prophylactic antiviral agent are allowed).
• Patients with any other serious/active/ uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to the first study drug dose.
• Patients with any other serious, life-threatening, or unstable preexisting medical condition (aside from the underlying malignancy) including significant organ system dysfunction or failure, clinically significant laboratory abnormality(ies), psychiatric disorder or altered mental status which, in the opinion of the Investigator, would either compromise the patient’s safety or interfere with obtaining informed consent, compliance with study procedures, or evaluation of the safety of the study drug(s).
• Prior therapy with irinotecan (effective with Protocol Version 3.0) or with:
  • Sub-study 1 and Sub-study 2: Anti-PD-(L)1, anti -LAG-3 * or anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other IO therapies. * Effective with Protocol Version 5.0, patients with prior anti-LAG-3 containing regimen are allowed. Prior anti-PD-(L)1 therapy may be allowed during the trial if regulatory approval for such therapy is obtained while this trial is enrolling;
  • Sub-study 3: Anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other IO therapies (other than anti-PD-(L)1 agents).
• Any antineoplastic agent for the primary malignancy (standard or investigational) with delayed toxicity within 4 weeks or 5 elimination half-lives, whichever is shortest, prior to the first study drug dose, except for nitrosoureas and mitomycin C within 6 weeks prior to the first study drug dose.
• Any other investigational treatments within 2 weeks prior to the study; this includes participation in any medical device or supportive care therapeutic intervention studies.
• Radiotherapy:
  • For target lesions within 4 weeks prior to the first study drug dose unless PD has been documented in the lesion following radiotherapy;
  • For non-target lesions within 1 week prior to the first study drug dose.
• Use of live and live-attenuated vaccines against infectious diseases (e.g., varicella) 4 weeks prior to the first study drug dose
• Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) within 2 weeks prior to the first study drug dose.
• Prophylactic use of hematopoietic growth factors within 1 week prior to the first study drug dose.
• Patients must not be on warfarin, strong cytochrome P450 (CYP) 3A4 inducers, strong CYP3A4 inhibitors, or strong UGT1A1 inhibitors.
  • Note: Discontinue at least 1 week prior to starting study drug combination therapy. Do not administer with irinotecan unless there are no therapeutic alternatives.
• Patients with a known or suspected hypersensitivity to any of the excipients of formulated study drug.
• Patients with unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy except for persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, lymphopenia, hypomagnesemia, and/or end-organ failure being adequately managed by hormone replacement therapy (HRT).
• Patients with inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to the first study drug dose.
• Patients with known or foreseeable inability, in the opinion of the Investigator, to comply with the protocol requirements.
• Sub-study 1 and Sub-study 2: Patients with known FGFR2 fusion or rearrangement, or IDH1 mutation.
• Sub-study 3: Patients with a history of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy. Investigators should ensure that all study enrollment criteria have been met prior to randomization/allocation and administration of the first study drug dose on Day 1. 

Eligibility last updated 4/18/22. Questions regarding updates should be directed to the study team contact.

• Over 18 years of age.
• Biologically female.
• Has consulted with Mayo Clinic’s department of Reproductive Endocrinology & Infertility.
• Has a BMI of ≥ 35.

• Minor (under 18 years of age).
• Not biologically female.
• Has not consulted with Mayo Clinic’s department of Reproductive Endocrinology & Infertility.
• Has a BMI of < 35.

• Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19.
• 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 adults ≥ 18 years of age at time of enrollment.
• Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen.
• Ongoing illness of any duration, and at least one of the following:
  • Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.).
  • Blood oxygen saturation (SpO2) ≤ 94% on room air.
  • Requiring supplemental oxygen.
  • Requiring mechanical ventilation or ECMO.
• Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60.
• Agrees to not participate in another intervention trial for the treatment of COVID-19 through Day 60.

• ALT or AST > 5 times the upper limit of normal.
• Estimated glomerular filtration rate (eGFR) < 30 mL/min (including patients receiving hemodialysis or hemofiltration).
• Neutropenia (absolute neutrophil count < 1000 cells/μL) (<1.0 x 10^3/μL or < 1.0 GI/L).
• Lymphopenia (absolute lymphocyte count < 200 cells/μL) (< 0.20 x 10^3/μL or < 0.20 GI/L).
• Pregnancy or breast feeding.
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
• Known Allergy to any study medication.
• Received cytotoxic or biologic treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], IL-17, or T-cell or B-cell targeted therapies (e.g., rituximab), tyrosine kinase inhibitors including baricitinib, TNF inhibitors, or interferon within 4 weeks or 5 half-lives prior to screening. Steroid dependency defined as need for prednisone at a dose > 10 mg (or equivalent) for > 1 month within 2 weeks of screening is exclusionary.
  • Note 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines.
  • Note 2: Infusion of convalescent plasma is also allowed.
• Based on medical history and concomitant therapies that would suggest infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
• Based on medical history and concomitant therapies that would suggest infection, suspected serious, active bacterial, fungal, viral (including, but not limited to, active HBV, HCV, or HIV/AIDS).
• Have received any live vaccine (that is, live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study.
  • Note: Use of non-live (inactivated) vaccinations is allowed for all participants.
• Severe hepatic impairment (defined as liver cirrhosis Child stage C).
• Current severe heart failure (New York Heart Association [NYHA] III-IV).
• In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.

• Able to understand and voluntarily sign an informed consent form (ICF).
• Male and female adults ≥ 18 years of age at the time of informed consent 
• Advanced solid malignancies for which no standard therapy is available. Subjects in whom available standard therapy is contraindicated may be eligible. 
• For Dose Expansion Phase
  •Expansion Group A:
  • Histologically confirmed unresectable locally advanced or metastatic (AJCC stage IIIB, IIIC, or IV) cutaneous malignant melanoma for which no standard therapy is suitable. 
• At least 1 measurable site of disease as defined per RECIST v1.1 criteria (Dose Expansion Phase) or evaluable disease (Dose Escalation Phase only).
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
• Life expectancy of > 12 weeks.
• Adequate hematologic status within 28 days prior to dosing as demonstrated by not requiring transfusion support or granulocyte-colony stimulating factor (G-CSF) to maintain: 
  • Absolute neutrophil count (ANC) ≥1.5 × 109/L
  • Platelet count ≥ 100 × 10^9/L 
  • Hemoglobin ≥ 90 g/L.
• Adequate liver function as demonstrated by:
  • Serum bilirubin < 2 × the upper limit of normal (ULN);
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN in subjects with liver metastases;
  • Gamma-glutamyl transferase ≤ 5 × ULN ;
  • Alkaline phosphatase ≤ 3 × ULN or ≤ 5 × ULN if bone or liver metastasis is present,
• Serum creatinine ≤ 1.5 × ULN or estimated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula.
• Prothrombin time (PT) (or International Normalized Ratio [INR]) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN or within the intended therapeutic range within 72 hours before the first dose of study drug in subjects receiving anticoagulant therapy.
• Willing and able to comply with scheduled visits, treatment plan, and laboratory tests.
• Absence of any other malignancy which has been active or treated within the past 3 years, except for cervical intraepithelial neoplasia, and nonmelanoma skin cancers (basal cell and squamous cell carcinomas).
• Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR agree to use a condom with spermicide and to not donate sperm during the study and for at least 90 days following last dose of PT01.
• Female subjects must be postmenopausal (>12 months without menses) or surgically sterile (ie,by hysterectomy and/or bilateral oophorectomy) or must be using highly effective contraception (ie, oral contraceptives, intrauterine device, double barrier method of condom and spermicide) and agree to continue use of contraception for 90 days after their last dose of PT01.
• Subjects who are of childbearing potential must have a negative serum pregnancy test at Screening and within 72 hours prior to the first dose.
• Peripheral forearm veins suitable for venous access including cannulation for infusion of PT01 and multiple blood sampling

• Received prior arginase or arginine deiminase therapy.
• Received recent anticancer therapy defined by: 
  • Chemotherapy, immunotherapy, hormonal therapy, and monoclonal antibodies (but excluding nitrosourea, mitomycin-C, targeted therapy) ≤ 28 days prior to starting study drug or who have not recovered from side effects of such therapy to Grade≤1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v4.03) except for subjects with alopecia; subjects receiving luteinizing hormone-releasing hormone agonists may be considered for enrollment after discussion with the Sponsor;
  • Last administration of nitrosourea or mitomycin-C ≤ 42 days prior to starting study drug or who have not recovered from the side effects of such therapy to Grade ≤ 1;
  • Targeted therapy (e.g., sunitinib, sorafenib, pazopanib) ≤ 14 days prior to starting study drug, or who have not recovered from the side effects of such therapy to Grade ≤ 1; 
  • Radiotherapy ≤ 28 days prior to starting study drug or ≤ 14 days prior to starting study drug in the case of localized radiotherapy (e.g., for analgesic purpose or for lytic lesions at risk of fracture) or who have not recovered from radiotherapy toxicities to Grade ≤ 1.
• Undergone major surgery (e.g., intrathoracic, intraabdominal, or intrapelvic), open biopsy, or significant traumatic injury ≤ 28 days prior to starting study treatment; subjects who have had minor procedures, percutaneous biopsies, or placement of vascular access device ≤ 7 days prior to starting study drug; or subjects who have not recovered from side effects of such procedure or injury.
• Uncontrolled concurrent illness including, but not limited to, ongoing or active serious infection requiring systemic antimicrobials (within 14 days prior to first dose), uncontrolled arterial hypertension (>160/100 mm Hg on antihypertensive medications), chronic pulmonary disease requiring oxygen, known bleeding disorders, uncontrolled endocrine diseases, altered mental status, or psychiatric illness/social situations that would limit compliance with protocol requirements.
• Significant cardiac or pulmonary disease defined by New York Heart Association Class III or IV, history of myocardial infarction within 6 months prior starting study drug, significant unstable arrhythmia, or evidence of ischemia on ECG.
• Symptomatic or uncontrolled brain metastases requiring current treatment (fewer than 28 days from last cranial radiation or from last steroids use).
• Healing or open wound(s).
• Lack of recovery of prior AEs to Grade ≤ 1 severity (except alopecia or lymphopenia) due to medications administered prior to the first dose of study drug.
• Any other condition or finding (including social situation) that, in the opinion of the Investigator, may render the subject to be either at excessive risk for treatment complications or not able to provide evaluable outcome information.
• Pregnant or breast-feeding women.
• Known allergy to any of the formulation components of PT01.

• Are 18 years of age or older.
• Have histologic evidence of locally or regionally advanced or stage IV malignancy.
• Are considered appropriate for starting therapy with anti-PD-1/anti-PD-L1 monoclonal antibody by their treating physician (prior therapy with ICI is allowed).
• Have an understanding of the protocol and its requirements, risks, and discomforts.
• Are willing to undergo peripheral blood collection at the time points mentioned in the protocol.
• Are able and willing to sign an informed consent.

• Patients under 18 years of age.
• Inability of the patient to understand the informed consent or be compliant with the protocol.
• Patients receiving any concurrent anti-cancer therapy or investigational agents (with the exception of an anti-PD-1/anti-PD-L1 agent as mentioned above).
• Patients who are pregnant, nursing, or are of childbearing potential and are unwilling to employ adequate contraception.

• Low Birth Weight (LBW) and/or Preterm infants and mothers. Admissions to either NICU will be screened based on gestational age or birth weight.
• Subjects included will be considered by birth weight (LBW, < 2500 grams), or gestational age (preterm, < 36 weeks). Subjects will be between the age of 3 days and 6 months old (corrected gestational age) at the time of enrollment. Cohort will be targeted to mother-infant dyads with infants born after March 2021 and ongoing through study fill.
• Cohort will be targeted to subjects with an anticipated duration of hospitalization 2 weeks or greater.
• Cohort will be targeted to subjects on a specified diet: either maternal milk, donor milk, or infant formula based.  
• Written informed consent will be obtained before enrollment.

• Major congenital anomalies involving the intestinal tract.
• Custodial issues that would prohibit consent.

Eligibility last updated 1/17/22. Questions regarding updates should be directed to the study team contact.

• Provide written informed consent.
• Completed Study AK002-016, defined as having received 6 infusions of study drug and followed through Day 176 (±3 days), or completed Study AK002-012, defined as having received the cohort-appropriate amount of doses and followed for 5 months after last dose of study drug.
• If patient is on pre-existing dietary restrictions, willingness to maintain those restrictions, throughout the study.
• Able and willing to comply with all study procedures.
• Female patients must be either postmenopausal for at least 1 year or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 3 months, or if of childbearing potential, have a negative pregnancy test and agree to use dual methods of contraception (partner with vasectomy is acceptable), or abstain from sexual activity until the end of the study, or for 120 days following last dose of study drug, whichever is longer.
• Male patients with female partners of childbearing potential must agree to use a highly effective method of contraception (vasectomy is acceptable) until the end of the study or for 120 days following last dose of study drug, whichever is longer. All fertile men with female partners of childbearing potential should be instructed to contact the Investigator immediately if they suspect their partner might be pregnant at any time during study participation.

• Poor tolerance to previous administration of AK002 in the opinion of the Investigator.
• Known hypersensitivity to any constituent of the study drug.
• Any disease, condition (medical or surgical), or cardiac abnormality, which, in the opinion of the Investigator, would place the patient at increased risk.
• Planned or expected vaccination with live attenuated vaccines during the treatment, or vaccination expected within 5 half-lives (4 months) of AK002 administration.
• Women who are pregnant, breastfeeding, or planning to become pregnant while participating in the study.
• Any other reason that in the opinion of the Investigator or Medical Monitor makes the patient unsuitable for enrollment.

Eligibility last updated 10/20/21. Questions regarding updates should be directed to the study team contact.