• Age 21-75 at time of screening.
• Patient scheduled for multilevel (> 3 levels) spinal fusion surgery with planned fixation to the pelvis using S2AI screws.
• Patient has signed study-specific informed consent form.
• Patient has the necessary mental capacity to participate and is physically able to comply with study protocol requirements. 

• Indication for multilevel spine fusion surgery is any of the following: 1. Congenital neuromuscular disease 2. Prior pelvic fixation (i.e., patient already has S2AI or iliac bolts in place, current surgery indicated to revise this hardware) 3. Grade IV spondylolisthesis.
• Prior sacroiliac joint fusion/fixation on either side.
• Presence of spinal cord stimulator.
• Presence of severe hip pain that could impair functional and quality of life improvement from complex spine surgery.
• Surgeon plans to use iliac screw for pelvic fixation.
• Any known sacral or iliac pathology.
• Any condition or anatomy that makes treatment with the iFuse Implant System infeasible.
• Known metabolic bone disease.
• Severe osteoporosis.
• Known allergy to titanium or titanium alloys.
• Use of medications known to have detrimental effects on bone quality and soft-tissue healing.
• Neurologic condition that would interfere with postoperative physical therapy.
• Current local or systemic infection that raises the risk of surgery.
• Patient currently receiving or seeking short- or long-term worker's compensation and/or currently involved in injury litigation related to the SI joint or low back pain.
• Currently pregnant or planning pregnancy in the next 2 years.
• Prisoner or a ward of the state.
• Known or suspected drug or alcohol abuse.
• Uncontrolled psychiatric disease that could interfere with study participation.
• Fibromyalgia.

Registration – Inclusion Criteria IUGR Cohort:

• Age ≥ 18 and ≤ 45 years at study entry.
• Diagnosis of IUGR before admission to labor and delivery.
• Ability to provide written informed consent.
• Weight greater than 110 pounds (50 kilograms, a standard requirement in obstetrics studies that include blood draws).
• > 28 weeks gestation.

Registration – Inclusion Criteria Control Cohort:

• Age ≥ 18 and ≤ 45 years at study entry.
• No known pregnancy complications at obstetrics visit (+/- 1 week gestational age of IUGR cohort).
• Ability to provide written informed consent.
• Weight greater than 110 pounds (50 kilograms, a standard requirement in obstetrics studies that include blood draws).
• > 28 weeks gestation.

Registration –

• Known immunodeficiency.
• Chronic, active viral infections, including HIV-1/2, HTLV-1/2, hepatitis B/C.
• Known autoimmune disease (e.g., rheumatoid arthritis or systemic lupus erythematosus).
• Solid organ or transplant recipient.
• Multiple gestations.
• Not planning on delivering at Mayo Clinic.
• Ruptured membranes.
• < 28 weeks gestation.

• At least 18 years of age.
• IMWG criteria for the diagnosis of a plasma cell disorder.

• Unable to provide consent.
• ECOG PS >2.
• Most recent hemoglobin < 8 g/dL within 30 days of the blood draw

• Be female, age 0-17 years.
• Be undergoing an elective laparoscopic oophorectomy or oophorectomy done via laparoscopy as part of their clinical care.
• Sign an approved informed consent and authorization permitting the release of personal health information. The patient and/or the patient’s legally authorized guardian must acknowledge in writing that consent for specimen collection has been obtained, in accordance with institutional policies approved by the U.S. Department of Health and Human Services.

• Girls with psychological, psychiatric, or other conditions which prevent giving fully informed consent.

• Patients over the age of 18 years.
• Ability to provide written, informed consent.

Exclusion Criteria:

• Known history of voice disorder or surgery that may alter voice characteristics.
• Smoking or vaping use currently or within the last 3 months.
• Chronic obstructive pulmonary disease.
• Prior esophageal or gastric surgical resection.
• PPI use within the last 8 weeks.
• Inability to speak (any cause).
• Upper respiratory tract infection, influenza, sinusitis, pharyngitis, tonsillitis, laryngitis or tracheitis within the last week.
• Pulmonary conditions including, bronchiectasis, pulmonary embolism (within last 3 months), idiopathic pulmonary fibrosis, interstitial lung disease, COPD exacerbation, asthma attack, pneumothorax, pleural effusion and/or respiratory failure.
• Recent chest trauma (last 30 days) resulting in rib fractures, sternum fracture.
• Respiratory conditions due to inhalation of chemicals, gases, fumes and vapors.
• Left-sided heart failure exacerbation.
• Intoxication, hepatic encephalopathy, delirium, coma, drowsiness.

Inclusion Criteria:

• Adult male or female ≥ 12 years of age at the time of informed consent or assent.
• Each subject and/or their parents or legal guardian (for adolescents), must read, understand and provide consent or assent together with their parent(s) or guardian signature (for adolescents) on the ICF for this study and be willing and able to adhere to study-related treatment regimens, procedures and visit schedule.
• Diagnosis or presumptive diagnosis of EoE that is confirmed during the Screening period by histology that demonstrates ≥ 15 peak eos/HPF. In order to ensure that a diagnosis can be made, at least 6 biopsies should be taken from both proximal and distal specimens (at least 3 each). Mid-esophageal biopsies are not required (optional). HPF will be defined as a standard area of 235 square microns in a microscope with 40x lens and 22mm ocular:
  • Esophagogastroduodenoscopies and biopsies are to be obtained during the Screening period;
  • Biopsies will be read by a central pathologist;
  • Esophagogastroduodenoscopies and biopsies performed outside the study will not be accepted to meet eligibility criteria;
  • Optional biopsies may be taken and processed locally for local use, only where specified in the local ICF. If serious pathology is unexpectedly encountered biopsies of such lesions must be processed locally.
• Have a subject-reported history of ≥ 6 episodes of dysphagia in the 14 days prior to baseline.
• Completion of the daily diary on at least 11 out of the 14 days during the 2-week Baseline Symptom Assessment.

• Have known contraindication, hypersensitivity, or intolerance to corticosteroids.
• Have a contraindication to, or factors that substantially increase the risk of, EGD procedure or esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 9 mm endoscope.
• Have history of an esophageal stricture requiring dilatation within the previous 12 weeks prior to Screening.
• Bone age more than 12 months behind chronological age for adolescent subjects.
• Have any physical, mental, or social condition or history of illness or laboratory abnormality that in the Investigator’s judgment might interfere with study procedures or the ability of the subject to adhere to and complete the study or increase the safety risk to the subject such as uncontrolled diabetes or hypertension or may increase risk of corticosteroid toxicity (e.g., abnormal bone mineral density).
• History of recurrent or current oral or esophageal mucosal infection due to inhaled or nasal corticosteroids.
• Have any mouth or dental condition that prevents normal eating.
• Have any condition affecting the esophageal mucosa or altering esophageal motility other than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles Classification of Gastroesophageal Reflux Disease;21, hiatus hernia longer than 3 cm, Barrett’s esophagus, and achalasia.
• Use of systemic (oral or parenteral) corticosteroids within 60 days before Screening, use of swallowed corticosteroids within 30 days before Screening.
• Initiation of either inhaled or nasal corticosteroids or high-potency dermal topical corticosteroids within 30 days before Screening
• Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 12 weeks before Screening.
• Use of potent cytochrome P450 (CYP) 3A4 inhibitors (eg, ritonavir and ketoconazole) in the 12 weeks before Screening.
• Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must remain stable after signing ICF).
• Morning (07:00 to 09:00, or as close to that window as possible) serum cortisol level ≤ 5 μg/dL (138 nmol/L) that is not responsive to ACTH stimulation: defined as a serum cortisol level < 16 μg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test using 250 μg cosyntropin administered intramuscularly (i.e., an abnormal result on the ACTH stimulation test).
• Use of biologic immunomodulators in the 24 weeks before Screening (allergy desensitization injection or oral therapy is allowed as long as the course of therapy is not altered during the study period).
• Subjects who have initiated, discontinued, or changed dosage regimen of histamine H2 receptor antagonists, antacids or antihistamines, leukotriene inhibitors or sodium cromolyn within 4 weeks before qualifying endoscopy. If already receiving these drugs, the dosage must remain constant throughout the study.
• Subjects who have changed dosage regimen of PPIs within 8 weeks before qualifying endoscopy. If already receiving PPIs, the dosage must remain constant throughout the study.
• Infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
• Have gastrointestinal bleeding or documented active peptic ulcer within 4 weeks prior to Screening or entering a new study period.
• Have chronic infection such as prior or active tuberculosis, active chicken pox or measles or absence of prior measles, mumps and rubella vaccine. Subjects with tuberculosis exposure or who live in high endemic areas should be assessed locally for tuberculosis before consideration for the study.
• Immunosuppression or immunodeficiency disorder.
• Current malignancy or malignancy within 3 years of Screening. Subjects in remission for at least 3 years post-treatment may be enrolled.
• Known severe bleeding disorder.
• Have a history or presence of Crohn’s disease, celiac disease, or other inflammatory disease of the gastrointestinal tract, including eosinophilic gastroenteritis.
• Have current drug abuse in the opinion of the Investigator.
• Have current alcohol abuse in the opinion of the Investigator.
• Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study.
• Sexually active females of childbearing potential who do not agree to follow highly effective contraceptive methods through the End of Study visit.
• Have received an investigational product, as part of a clinical trial within 30 days (or 5 halflives, whichever is longest) of Screening. Subjects who are currently participating in observational studies or enrolled in patient registries are allowed in this study.
• Have participated in a prior study with investigational product APT-1011.

• Informed consent or assent (if applicable).
• Provision of signed and dated, written informed consent form or assent form (if applicable) prior to any mandatory study specific procedures, sampling, and analyses.
• Provision of signed and dated written Genetic informed consent prior to collection of sample for genetic analysis for adult patients.
• Patients 12 to 65 years of age, inclusive, at the time of signing the informed consent or assent (if applicable) form.
• Documented previous diagnosis of EoE by endoscopy (documented diagnosis defined as
• an esophageal count of ≥ 15 eos/hpf on at least 1 esophageal level) and confirmed diagnosis by a centrally-read esophageal biopsy for the purposes of this study (confirmed diagnosis defined as an esophageal count of ≥ 15 eos/hpf at 2 or more esophageal levels).
• Two to 4 biopsies should be obtained from both the proximal and distal esophagus.
• Biopsies can be taken from the mid-esophagus for additional evaluation.
• Must be symptomatic at Visit 1 (run-in period) and Visit 2 (randomization):
  • A patient reported average of at least 2 days per week with an episode of dysphagia over the 4 weeks prior to the run-in period; AND
  • At least 2 days with an episode of dysphagia (Daily DSQ ≥2) per week between Visit 1 and the Visit 2 (randomization).
• Must be adherent to daily diary assessments:
  • Must complete 70% of daily diaries between Visit 1 and Visit 2; AND
  • Must have completed at least 8 of 14 daily diaries in the 14 days prior to randomization.
• May be on background medications for EoE and related treatments during the study as long as the background medications have been stable for at least 4 weeks prior to the run-in period and there is agreement not to change type of background medication or dosage for the first 52 weeks of the study unless medically indicated. Patients on PPI therapy must report a stable dose for at least 8 weeks prior to the run-in period..
• Body weight of at least 35 kg.
• Negative serum pregnancy test for female patients of childbearing potential at Visit 1 (enrollment).
• Women of childbearing potential (WOCBP) must agree to use a highly effective form of birth control (confirmed by the Investigator) from randomization throughout the study duration and within 16 weeks after last dose if IP. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Highly effective forms of birth control include:
  • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation- oral, intravaginal, or transdermal;
  • Progestogen-only hormonal contraception associated with inhibition of ovulationoral, injectable, or implantable;
  • Intrauterine device (IUD);
  • Intrauterine hormone-releasing system (IUS);
  • Bilateral tubal occlusion;
  • Sexual abstinence; i.e., refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient);'
  • Vasectomized sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomized partner has received medical assessment of the surgical success).
• Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for ≥ 12 months prior to the planned date of randomization without an alternative medical cause. The following age-specific requirements apply:
  • Women < 50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.  Until FSH is documented to be within menopausal range, treat the patient as WOCBP;
  • Women ≥ 50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.

• As judged by the Investigator, any evidence of a medical illness which, in the Investigator’s opinion, makes it undesirable for the patient to participate in the study.
• Other GI disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, or celiac disease.
• Any clinical significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during run-in period which, in the opinion of the Investigator, may put the patient at risk, because of his/her participation in the study, or may influence the results of the study, or the patients’ ability to complete entire duration of the study.
• Esophageal stricture that prevents the easy passage of a standard endoscope or any critical esophageal stricture that requires dilation during the run-in period.
• Ise of a feeding tube, or not eating solid food daily during the run-in period.
• Hypereosinophilic syndrome, defined by multiple organ involvement and persistent blood eosinophil count >1500 eos/μL.
• EGPA vasculitis.
• Eosinophilic gastritis, gastroenteritis, enteritis, or colitis documented by biopsy.
• Current malignancy, or history of malignancy, except for:
  • Patients who have had basal cell carcinoma, localized squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided that the patient is in remission and curative therapy was completed at least 12 months prior to the date informed consent, and assent when applicable was obtained.
• Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent, and assent when applicable, was obtained.
• History of anaphylaxis to any biologic therapy or vaccine.
• Current active liver disease:
• Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen
• [HBsAg] or hepatitis C antibody), or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 3 times the upper limit of normal (ULN), confirmed by repeated testing during the run-in period.
• Transient increase of AST/ALT level that resolves by the time of randomization is acceptable if in the Investigator’s opinion the patient does not have an active liver disease and meets other eligibility criteria.
• Helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent or assent (if applicable) is obtained that has not been treated with or has failed to respond to standard of care therapy.
• History of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
• Concomitant use of immunosuppressive medication (including but not limited to:
• methotrexate, troleandomycin, cyclosporine, azathioprine, and systemic corticosteroids.
• Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent or assent (if applicable) is obtained.
• Receipt of live attenuated vaccines 30 days prior to date of informed consent or assent (if applicable).
• Receipt of any marketed or investigational biologic (monoclonal or polyclonal antibody) within 4 months or 5 half-lives prior to the date informed consent or assent (if applicable), is obtained, whichever is longer, and during the study period.
• Previous participation in a benralizumab clinical study.
• Known history of allergy or reaction to any component of the IP formulation.
• Receipt of any investigational drug within 30 days or 5 half-lives prior to randomization, whichever is longer.
• Initiation or change of a food-elimination diet regimen or re-introduction of a previously eliminated food group in the 6 weeks prior to start of the run-in period.
• For women only: Currently pregnant, breastfeeding, or lactating women.
• A serum pregnancy test will be done for women of childbearing potential at screening and a urine pregnancy test must be performed for women of childbearing potential at each treatment visit prior to IP administration. A positive urine test result must be confirmed with a serum pregnancy test. If serum test is positive, the patient should be excluded.

• 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.

• Having undergone an right heart catheterization (RHC) within 18 months (prevalent PH participants) or 6 months (prevalent non-PH participants) or have undergone or planned RHC within 6 weeks (incident participants). The results of the incident RHC (incident participants) or the most recent RHC (prevalent participants) will be used to classify the participant in one of the above study population categories.
• Medically stable on the basis of physical examination, medical history and vital signs performed at screening. Any abnormalities must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and initialed by the investigator.
• Must sign an Informed Consent Form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
• Must sign a separate ICF (or their legally-acceptable representative must sign) if he or she agrees to provide an optional (deoxyribonucleic acid [DNA]) sample for research (where local regulations permit). Refusal to give consent for the optional (DNA) research sample does not exclude a participant from participation in the study.

• Participants requiring renal dialysis.
• History of lung or heart transplant (waiting list status or consideration of enlisting is allowed).
• Participants unable to breathe room air without supplemental oxygen for at least 10 minutes (for breath collection).
• Severe left ventricular dysfunction: Left ventricular ejection function less then (<) 35 percent (%).
• Participants who are immunocompromised.

• Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
• Ki67 index ≥ 10 and ≤ 55%
• Patients ≥ 15 years of age and a body weight of > 40 kg at screening
• Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization:  [68Ga]-DOTA-TOC (e.g., Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging,  [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g., NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT),  SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging.
• The tumor uptake observed in the target lesions must be > normal liver uptake observed on planar imaging.
• Karnofsky Performance Score (KPS) ≥ 60.
• Presence of at least 1 measurable site of disease.
• Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities.

• Creatinine clearance < 40 mL/min calculated by the Cockroft Gault method.
• Hb concentration < 5.0 mmol/L (< 8.0 g/dL); WBC < 2 x 10E^9/L (2000/mm^3); platelets < 75 x 10E^9/L (75x10E3/mm^3).
• Total bilirubin > 3 x ULN.
• Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range.
• Pregnancy or lactation.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 6 months after study drug discontinuation.
• Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
• Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization.
• Patients for whom, in the opinion of the investigator, other therapeutic options (e.g., chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics.
• Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies of GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.
• Any previous radioembolization, chemoembolization and radiofrequency ablation.
• Any surgery within 12 weeks prior to randomization in the study.
• Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.
• Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient’s measured cardiac ejection fraction in these patients must be >40% before randomization.
• QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome.
• Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%.
• Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment.
• Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (e.g., octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera, unless the tumor uptake on target lesions observed by study-permitted somatostatin receptor imaging (SRI) modalities during continued long-acting SSA treatment is greater than the liver uptake observed by planar imaging.
• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
• Prior external beam radiation therapy to more than 25% of the bone marrow.
• Current spontaneous urinary incontinence.
• Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
• Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
• Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.
• Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days.

Eligibility last updated 2/28/22. Questions regarding updates should be directed to the study team contact.

• 18 years of age or older.
• MR ≥ 3+ as assessed by the Echo Core Lab (See MAC Registry).
• NYHA functional class ≥ II.
• Per the Heart Team, commercially available surgical or transcatheter treatment options are deemed unsuitable due to clinical, anatomic or technical considerations.
• Subject’s heart failure management has been optimized based on subject characteristics and applicable guidelines, and stable for at least 30 days prior to enrollment.
  • Note: Subjects who require significant changes to heart failure medication after enrollment but prior to the procedure must re-stabilize for 30 days to be eligible.
• The subject or subject’s legal representative has been informed of the nature of the study, agrees to its provisions and has provided written informed consent.

• Mitral/cardiac anatomy that would preclude appropriate delivery and deployment of the dock or valve, including but not limited to:
  • Annular dimensions that could potentially increase the risk of paravalvular leak (as assessed by Computed Tomography [CT] core lab);
  • Commissural jet or lateral commissural flail/prolapse that could potentially increase the risk of paravalvular leak;
  • Medial commissural flail or prolapse;
  • Calcification that would interfere with the SAPIEN M3 System during delivery or after implantation; if potential for interference is uncertain, see MAC Registry;
  • Interatrial septum or left atrium not suitable for transcatheter trans-septal access;
  • LVEDD ≥ 75 mm as assessed by Echo core lab;
  • Sub-valvular anatomy that is unsuitable for dock encircling as assessed by CT core lab;
  • Significant risk of LVOT obstruction as assessed by CT core lab.
• Inappropriate anatomy for femoral introduction and delivery of the SAPIEN M3 Dock and Valve
• Presence of any device that will contact or interfere with the SAPIEN M3 System during delivery or after implantation.
• LVEF < 25% as assessed by Echo core lab.
• Severe right ventricular dysfunction as assessed by Echo core lab.
• Need for aortic, tricuspid or pulmonic valve intervention within the next 12 months.
• History of heart transplant.
• Cardiac imaging evidence of intracardiac mass, thrombus or vegetation.
• Active bacterial endocarditis within 180 days of the procedure.
• Hemodynamic instability requiring inotropic or mechanical support within 30 days of the procedure.
• Myocardial infarction within 30 days of the procedure.
• Clinically significant untreated coronary artery disease requiring revascularization.
• Any percutaneous cardiovascular intervention, cardiovascular surgery, or carotid surgery within 30 days of the procedure; TEER procedures are excluded regardless of timeframe (See Failed TEER Registry).
• Stroke or transient ischemic attack within 90 days of the procedure.
• Irreversible, severe pulmonary hypertension (e.g., pulmonary artery systolic pressure ≥ 2/3 systemic pressure).
• Chronic obstructive pulmonary disease (COPD) requiring home oxygen therapy or chronic outpatient oral steroid use.
• Renal insufficiency (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m^2 ) or receiving renal replacement therapy.
• Liver disease (cirrhosis of the liver [Child-Pugh class B or C]).
• Planned surgery within the next 12 months.
• Inability to tolerate or a medical condition precluding treatment with antithrombotic (antiplatelet, anticoagulant) therapy, including heparin administration during the procedure.
• Active infection requiring current antibiotic therapy (if temporary illness, subject may be a candidate 2 weeks after discontinuation of antibiotics).
• Active SARS-CoV-2 infection (Coronavirus-19 [COVID-19]) or previously diagnosed with COVID-19 with sequelae that could confound endpoint assessments (as assessed by the Case Review Board).
• Leukopenia (White Blood Cells < 3000 cells/mL), anemia (Hemoglobin < 9 g/dL), thrombocytopenia (platelet < 50,000 cells/mL), history of bleeding diathesis or coagulopathy, or hypercoagulable states
• Refusal of blood products.
• Female who is pregnant or lactating.
• Estimated life expectancy < 12 months due to non-cardiac conditions.
• Participating in another investigational drug or device study that has not reached its primary endpoint.
• Subject considered to be part of a vulnerable population.

Eligibility last updated 5/2/22. Questions regarding updates should be directed to the study team contact.

• Adult patients (≥ 18 years old) referred to our Mayo Clinic chronic cough specialty clinic.
• Diagnosis of chronic cough > 8 weeks as per ACCP guidelines. This could include different etiologies such as cough variant asthma, eosinophilic bronchitis, GERD, UACS and CHS.
• Chronic refractory cough or unexplained cough for at least 1 year prior to screening per American College of Chest Physicians/ British Thoracic Society (ACCP/BTS) guidelines.

Exclusion Criteria: 

• Patients without research authorization.
• Patients < 18 years of age.
• Patients with acute respiratory tract infection.
• Patients with asthma or COPD exacerbation at the visit.
• Pregnant or lactating women.
• Active smokers using cigarettes, vaping or electronic cigarettes.
• Patients on use of angiotensin receptor inhibitors.
• Patients with pulmonary fibrosis.
• Patients with bronchiectasis.
• Patients with lung cancer.
• Patients in their end of life care.

• Adults ≥ 65 years of age.
• Participants must be physically capable (defined as easy to moderate physical activities daily at least 60 minutes).
• Participants must have a normal (18.5-24.9kg/m^2) or overweight BMI (25-29.9kg/m^2).
• Participants must be able to speak, listen, read, and understand sentences written in English.

• Participants will be excluded who:
  • display more than two risk factors for coronary artery disease;
  • have a history of falls, osteoporosis, osteoarthritis, or orthopedic or neurological conditions (i.e., stroke);
  • take medications that cause dizziness or slow movement;
  • smoke;
  • have a body mass to height squared ratio greater than 30kg/m2 or less than 18.4kg/m^2;
  • blood pressure greater than 140/90 mmHg;
  • history of heart conditions.
• Individuals with progressive cognitive, neurologic disorders, cancer treatment, chronic heart failure, or unstable medical conditions.

• Individuals ≥ 18 and ≤ 60 years of age.
• Otherwise healthy subjects using intramural and local extramural advertising after approval from the Mayo Clinic Institutional Review Board.
• Individuals who express interest in participating will be invited for a screening visit. 

• Age < 18 or > 60.
• BMI < 19 or >40 kg/m^2.
• Medication that can affect glucose metabolism (determined by PI).
• Any chronic illness.
• Upper GI surgery.
• History of diabetes (FBG > 100 mg/dL).

Eligibility last updated 12/2/21. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.
• Acute myocardial infarction, STEMI and NSTEMI.
• Ability to use the device at home.
• Must have smartphone device with home wi-fi/internet available which allow 24-7 ability to transmit ECG.
• Caring family member who will be able to perform the ECG in case the patient himself/herself won't be able to do it.

• No ability to use the device at home.
• No smartphone device or home wi-fi/mobile internet which prevent 24/7 ability to transmit ECG.
• Cannot download the smartheart app.
• No support in home environment.
• Out of hospital cardiac arrest: secondary to a non-shockable rhythm, unrelated to an acute coronary syndrome, or with any level of neurologic damage.
• Resident of nursing home or acute care facility
• Uninterpretable ECG at discharge – left bundle branch block (LBBB), pacemaker or implantable cardioverter defibrillator (ICD) with pacing dependence.
• Patients who are planned for staged PCI after the index hospitalization.

Eligibility last updated 1/13/22. Questions regarding updates should be directed to the study team contact.

• Age 18-80 years, male, female, any race/ethnicity.
• Diagnosis of bipolar I disorder or bipolar II disorder, or bipolar (BP) schizoaffective defined by DSM-IV or DSM-V criteria, SCID- confirmed. If patient has already completed a DSM-IV or DSM-V SCID within one year of enrollment, they will not be required to repeat the SCID assessment.
• Ability for a referring clinician or research clinician to complete a retrospective clinical assessment of response to lithium, mood stabilizing anticonvulsants(carbamazepine, oxcarbamazepine, divalproex sodium, lamotrigine, zonisamide) typical and atypical antipsychotics, stimulants and related compounds (modafinil / armodafinil) and, unimodal antidepressants utilizing the Alda scale.

• Inability to speak English.
• Inability or unwillingness to provide informed consent or scoring less than 80% on the comprehension assessment (CA) form.
• Unwilling to consent to providing biospecimens to be stored in the biobank for an indefinite amount of time and to be used in future research studies of as yet unknown design.
• Actively psychotic or suicidal symptoms.
• Involuntary patients.

• Age ≥ 45 and ≤ 75 years old AND
• AA race (self-identified) and/or first-degree relative of a patient with a plasma cell dyscrasia such as MGUS, SMM, MM, and Waldenström’s Macroglobulinemia, or another blood cancer.
• For participants with a strong family history (2 relatives with blood cancers, their first- and second-degree relatives will be allowed to participate if 18 years or older.

• Persons diagnosed with cancer at any site (including hematologic cancers) with symptomatic disease requiring active therapy.
• Persons diagnoses with an already diagnosed plasma cell dyscrasia such as MGUS, SMM, MM, and Waldenström’s Macroglobulinemia.
• First degree relatives would not need to be identified by the participant. 
• We will include all special populations who fall within the eligible high-risk age range,  ≥ 40 and ≤ 75 including adults unable to consent, pregnant women, and prisoners.  These populations will not be excluded as this is a non-therapeutic study.

• Aged 18 years or older at the time of consent to participate in the study.
• Clinical confirmed diagnosis of CF or NCFB per clinical records and guidelines of the CF Foundation or European Respiratory Society (ERS), respectively, for at least 12 months.
• Positive sputum culture for PA or SA (not both) at screening.
• Forced expiratory volume in 1 second (FEV1) ≥ 50% at screening.

For participants with NCFB:

• Not taking chronic inhaled and/or oral antibiotics at screening.

For participants with CF:

• Taking no or only one chronic inhaled antibiotic on alternating months at screening.
• CF patients taking CFTR channel modulators are permitted in the study.

• Currently participating in vaccine studies or interventional studies for respiratory infections/diseases.
• Has been taking systemic antibiotics within 30 days prior to screening.
• Clinically significant and unstable cardiovascular, respiratory, renal, gastrointestinal, hematologic, neurologic, endocrinologic, oncologic, ophthalmologic, musculoskeletal, psychiatric or any other uncontrolled medical illness at screening.
• Underwent lung transplantation.
• Positive sputum culture for PA or SA and for other pathogens (e.g., Burkholderia spp., H. influenzae, S. pneumoniae, etc.) at screening. Participants who are co-colonized with PA and SA or with PA or SA and with other bacteria are also excluded.
• History of positive sputum culture for non-tuberculous mycobacterium within the previous 6 months.
• Any condition for which, in the opinion of the investigator, participation would not be in the best  interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
• Any physical abnormality which limits the ability to collect regular sputum specimens.

Cancer patients who have received cancer treatment.

• Male or female.
• Ages 18-85.
• Provision of signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Is enrolled in ALLFTD.
• Is a member of a family with a known mutation in C9orf72, GRN or MAPT.

• Any permanent contra-indication to repeated blood draws, such as poor venous access.
• Any conditions or circumstances which, in the opinion of the investigator, would not allow participation in the study.

• Patients must have a diagnosis of pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma, ganglioglioma, optic pathway glioma, diffuse astrocytoma, low-grade neuroepithelial tumor, low-grade glioneuronal tumor or LGG, NOS, after central pathology review.
• Patients must have had histologic verification of disease at original diagnosis or recurrence EXCEPT for patients with optic pathway gliomas. Patients with optic pathway gliomascan be enrolled without histologic verification but with radiologic verification.
• For recurrent tumors that enhance but were originally non-enhancing or if there is a high index of suspicion regarding high-grade transformation, repeat biopsy is required.
• Tumor must be located in or adjacent to the suprasellar region or midline structures. Midline structures include, but are not limited to: the thalamus, basal ganglia, internal capsule, medial temporal lobe, midbrain, tectum, third ventricle, fourth ventricle, cerebellum, pons, and medulla. Tumors may involve the optic pathway. For questions about tumor locations that are not specified on this list, please contact the Study PI.
• Patients must be aged 6 to < 22 years of enrollment.
• Patients must have a performance status greater or equal to 70 (use Karnofsky scale for patients aged 16 years and greater and Lansky scale for patients aged less than 16 years).
• Patients may not receive concurrent chemotherapy or targeted therapy, including but not limited to BRAF-inhibitors and MEK-inhibitors.
• All patients must be able to undergo contrast-enhanced brain MRI.
• Patients with seizures may be enrolled if well controlled on anticonvulsants.

• Patients who have received prior CNS radiation.
• Patients with gross total resection and no measurable disease on MRI.
• Patients with evidence of metastatic disease.
• Patients with WHO grade II midline tumors that harbor the H3K27M mutation, IDH-mutant gliomas, grade II ependymomas and subependymomas, pituicytomas, spindle cell oncocytomas, or granular cell tumors of the sellar region.
• Patients with tumors that directly invade bilateral hippocampi or with gross tumor volumes that extend into bilateral hippocampi.
• Patients with tumors in the spine or cervicomedullary junction.
• Females of child-bearing potential cannot be pregnant or breast feeding. Female participants > 10 years of age or post menarche must have a negative serum or urine pregnancy test before enrollment. Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
• Patients with NF-1.
• Patients who are status post resection of bilateral hippocampi. Patients who are status post resection of one hippocampus will be eligible for the study and the hippocampal dose constraints will be applied to the intact hippocampus.
• Patients who are not able to undergo neuro-cognitive testing, including children lacking English comprehension or children with premorbid neurological/neurodevelopmental disorders such as Down’s syndrome or autism.

• Ability of the participant and/or his/her legally authorized representative (e.g., parent, spouse, or legal guardian), as appropriate and applicable, to understand the purpose and risks of the study, to provide signed and dated informed consent, and to authorize the use of confidential health information in accordance with national and local privacy and ethics regulations.
• Participant was participating in an aducanumab clinical study at the time of the announcement of early termination (feeder studies).
  • Note #1: Participants who formerly participated in feeder studies and had to permanently discontinue the investigational product and/or exited a feeder study due to protocol mandatory requirements for discontinuation that are no longer applicable at the time of screening will be evaluated by the Sponsor on a case-by-case basis.
  • Note #2: Participants who completed screening in Study 221AD205 and were confirmed eligible prior to 21 March 2019 but were not randomized due to the discontinuation of the trial may have the opportunity to screen on this study upon review/approval from the Sponsor.
• Must have the ability to comply with protocol-related tests and procedures and have an MMSE score above 10 at Screening.
• Has one care partner who, in the Investigator’s opinion, has adequate contact with the participant as to be able to provide accurate information about the participant’s cognitive and functional abilities. The care partner must be available to provide information to the Investigator and site staff about the participant and attend in-person clinic visits that require care partner input for clinic assessments. The care partner should be available for the duration of the study.
• Female participants of childbearing potential must practice effective contraception during the study and for 5 times the half-life or 24 weeks (whichever is longer) after their last dose of study treatment.
• Apart from a clinical diagnosis of Alzheimer’s disease, the participant must be in good health as determined by the Investigator, based on medical history and screening assessments.

• Any uncontrolled medical or neurological/neurodegenerative condition (other than Alzheimer’s disease) that, in the opinion of the Investigator, might be a contributing cause of the participant’s cognitive impairment (e.g., substance abuse, vitamin B12 deficiency, abnormal thyroid function, stroke or other cerebrovascular condition, Lewy body dementia, fronto-temporal dementia, head trauma).
• Clinically significant unstable psychiatric illness (e.g., uncontrolled major depression, uncontrolled schizophrenia, uncontrolled bipolar affective disorder) within 6 months prior to Screening.
• Stroke or any unexplained loss of consciousness within 1 year prior to Screening.
• Brain MRI (performed at Screening, centrally read) evidence of any of the following:
  • Acute or subacute hemorrhage;
  • Prior macro-hemorrhage (defined as > 1 cm in diameter on T2* sequence) or prior subarachnoid hemorrhage unless it can be documented that the finding is not due to an underlying structural or vascular abnormality (i.e., finding does not suggest participant is at risk of recurrent hemorrhage);
  • Greater than 4 (for treatment-naïve participants) or ≥ 10 (for aducanumab previously treated participants) micro-hemorrhages (defined as ≤ 1 cm in diameter on T2* sequence);
  • Cortical infarct (defined as > 1.5 cm in diameter; irrespective of anatomic location);
  • Any focal area of superficial siderosis (for treatment-naïve participants) or 3 or more focal areas of superficial siderosis (for aducanumab previously treated participants).
  • History of bleeding disorder or predisposing conditions, blood clotting, or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator.
• Presence of diabetes mellitus that, in the judgment of the Investigator, cannot be controlled or adequately managed.
• History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class III or IV), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year prior to Screening.
• Clinically significant 12-lead ECG abnormalities, as determined by the Investigator.
• Uncontrolled hypertension defined as: average of 3 SBP/DBP readings > 165 mmHg and/or > 100 mmHg at Screening (blood pressure measurements exceeding these limits may be repeated as warranted by the Investigator, but values must be within the specified limits for the participant to be eligible for the study), or persistent SBP and/or DBP readings > 180 mmHg and/or >100 mmHg, respectively, 3 months prior to treatment (Day 1) that, in the opinion of the Investigator, are indicative of chronic uncontrolled hypertension.
• History of malignancy or carcinoma. The following exceptions may be made after discussion with the Sponsor:
  • Participants whose cancer is in remission according to the cancer specialist prior to Screening;
  • Participants with a history of excised or treated basal cell or squamous carcinoma of the skin.
• A seizure event that occurred after the last visit of the feeder study and before Screening for this study.
• Evidence of impaired liver function as shown by an abnormal liver function profile at Screening (e.g., repeated values of AST and ALT ≥ 2 × the upper limit of normal).
• History or evidence of an autoimmune disorder considered clinically significant by the Investigator or requiring chronic use of systemic corticosteroids or other immunosuppressants.
• Recent history (within 1 year of Screening) of alcohol or substance abuse as determined by the Investigator, a positive urine drug (due to nonprescription drug) or alcohol test at Screening or use of cannabinoids (prescription or recreational).
• Clinically significant systemic illness or serious infection (e.g., pneumonia, septicemia) within 30 days prior to or during Screening.
• History of or known seropositivity for HIV.
• Current hepatitis C infection (defined as positive HCV antibody and detectable HCV RNA. Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (Reference: United States Centers for Disease Control and Prevention).
• Current hepatitis B infection (defined as positive for HBsAg and/or total anti-HBc). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
• History of severe allergic or anaphylactic reactions, or history of hypersensitivity to any of the inactive ingredients in the drug product (refer to the IB for information on the clinical formulation).
• Any other medical conditions (e.g., renal disease) that are not stable or controlled, or, which in the opinion of the Investigator, could affect the participant’s safety or interfere with the study assessments.
• Use of any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, put the participant at higher risk for AEs, or impair the participant’s ability to perform cognitive testing or complete study procedures.
• Use of allowed medications for chronic conditions at doses that have not been stable for at least 4 weeks prior to Screening up to Day 1, or use of Alzheimer’s disease medications (including but not limited to donepezil, rivastigmine, galantamine, tacrine, and memantine) at doses that have not been stable for at least 8 weeks prior to Screening up to Day 1.
• Chronic use of systemic immunosuppressive drugs (including systemic corticosteroids). Local and/or topical immunosuppressants will be allowed.
• Use of chemotherapeutic agents and checkpoint inhibitors.
• Use of parenteral immunoglobulin, blood products, plasma derivatives, plasma exchange, or plasmapheresis.
• Use of vaccinations within 10 days prior to Day 1.
• Use of medications with platelet anti-aggregant or anticoagulant properties (the use of aspirin at a dose ≤ 325 mg daily is allowed).
• Use of illicit narcotic medication.
• Participation in any study in which the participant is taking an investigational product for Alzheimer’s disease (with purported disease-modifying treatment or not) unless the participant has fulfilled a wash-out period of at least 5 half-lives for that particular investigational product or is able to provide documentation of having received placebo in that investigational product study.
• Contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed).
• Only for participation in the PET substudies:
  • Contraindication to having a PET scan (e.g., inability to lie flat or still for the duration of the scan) or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to PET ligand or imaging agent, failure to participate in and comply with previous PET scans);
  • Have had or plan exposure to experimental radiation within 12 months prior to Screening such that radiodosimetry limits would be exceeded by participating in this study.
• Only for participants who consent to LP: any contraindications to having an LP (e.g., platelet count < 100,000/µL, lumbar spine deformity). Any symptoms caused by or related to the optional LP during Screening must be resolved prior to Day 1. Participants may still participate in the overall study even if participation in the optional LP portion is contraindicated. Others
• Female participants who are pregnant or currently breastfeeding.
• Participant currently living in an organized care facility with extensive intervention and/or support of daily living activities.
• Blood donation (≥ 1 unit) within 1 month prior to Screening
• Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the participant unsuitable for enrollment.

• Patients must have histologically or cytologically confirmed small bowel adenocarcinoma. Ampullary adenocarcinomas are not eligible. Patients must have metastatic disease or locally advanced unresectable disease.
• Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to registration. Patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration.
• Patients must have measurable or non-measurable disease. All scans needed for assessment of measurable disease must be performed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.
• Patients must have progressed on prior therapy with a fluoropyrimidine and/or oxaliplatin, given either for metastatic/locally advanced disease or as adjuvant therapy completed within the previous 12 months.
• Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to registration and all toxicity must be resolved to grade 1 (with the exception of grade 2 neuropathy) prior to registration. In Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 2 sensory neuropathy is defined as "moderate symptoms; limiting instrumental activities of daily living (ADLs)."
• Patients must have a complete medical history and physical exam within 28 days prior to registration.
• Patients must have a Zubrod performance status of 0 or 1.
• Absolute neutrophil count (ANC) ≥ 1,500/mcL (must be obtained within 28 days prior to registration).
• Platelets ≥ 100,000/mcL (must be obtained within 28 days prior to registration).
• A total bilirubin ≤ 1.5 x institutional limit normal (IULN) (must be obtained within 28 days prior to registration).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) ≤ 3.0 x IULN (or 5.0 x IULN if liver metastases are present) (must be obtained within 28 days prior to registration).
• Serum creatinine ≤ 1.5 x IULN OR calculated creatinine clearance ≥ 40 mL/min (must have been obtained within 28 days prior to registration).
• Patient must have urinary protein  1+ on dipstick or routine urinalysis (UA) within 28 days prior to registration. If dipstick or routine analysis is ≥ 2+, a 24
  •hour urine collections for protein must demonstrate < 1000 mg of protein in 24 hours.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients must not have known dihydropyrimidine dehydrogenase deficiency.
• Patients must be offered the opportunity to participate in specimen banking.
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

• Patients must not have received prior treatment with irinotecan, taxane, or ramucirumab for small bowel adenocarcinoma.≤
• Patients must not have had major surgery within 28 days prior to registration, or minor surgery within 7 days prior to registration, and must not be planned for elective major surgery to be performed during protocol treatment.
• Patients must not be currently enrolled in or have discontinued within the last 28 days a clinical trial involving an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Patients participating in surveys or observational studies are eligible to participate in this study.
• Patients must not be receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents.
• Patient must not have a known bleeding diathesis. 
• Patient must not have uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mg HG diastolic for > 4 weeks) despite standard medical management -Patient tumors must not have known deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H).
• Patients must not be pregnant or nursing and must have had a negative pregnancy test within 4 weeks of starting treatment. Women/men of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
• Patients must not have an active infection requiring systemic therapy.
• Patient must not have liver dysfunctions manifested by either (1) Child-Pugh B (or worse) or (2) cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
• Patients must not have a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 90 days prior to registration.
• Patients must not have experienced any arterial thrombotic event (including but not limited to myocardial infarction, unstable angina, stable angina markedly limiting ordinary physical activity, cerebrovascular accident, or transient ischemic attack) within 120 days prior to registration.
• Patients must not have a prior history of gastrointestinal (GI) perforation/fistula or other risk factors for perforation within 120 days prior to registration.
• Patients must not have experienced any grade 3-4 GI bleeding within 90 days prior to registration.
• Patient must not have experienced any serious or non-healing wound, ulcer, or bone fracture within 28 days prior to registration.

• Male or female, aged ≥ 18 years.
• Confirmed diagnosis of:
  • For the monotherapy cohorts: Metastatic or unresectable BC, NSCLC, CRC, ovarian cancer, or acral melanoma that is refractory to standard therapy or for which no standard therapy exists. Participants who are considered intolerant of or ineligible for standard therapy(ies), as well as participants who have been offered but refused standard therapy(ies), may also be eligible;
  • For the pembrolizumab combination therapy cohort: Metastatic or unresectable NSCLC, CRC (only MSI-H or dMMR), melanoma (with the exception of uveal melanoma), HCC, HNSCC, ESCC, or UC with prior or ongoing pembrolizumab treatment and have progressed or have achieved stable disease and who, in the judgment of their treating physicians, could benefit from the addition of ATRC-101 to improve or maintain their response:
  • Individuals with BRAF mutant melanoma must have received BRAF inhibitors alone or in combination with a MEK inhibitor, if indicated;
  • Individuals with NSCLC should have received platinum-based therapy unless contraindicated.
  • For the PLD combination therapy cohort: Metastatic or unresectable high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum resistant, defined as progression during or within 6 months of the last dose of platinum-based chemotherapy OR BC that is refractory to other standard therapies.
• Measurable disease based on RECIST v1.1, as assessed by the local site investigator/radiologist. Lesions situated in an area treated with radiation or other locoregional therapy are considered measurable only if the progression has been demonstrated in such lesions following loco-regional therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate organ and marrow function (i.e., without chronic, ongoing growth factor or transfusion support) at Screening as defined by the following laboratory parameters:
  • Absolute neutrophil count (ANC) ≥ 1000/µL;
  • Absolute lymphocyte count (ALC) ≥ 500/ µL;
  • Platelet count ≥ 75,000/µL;
  • Hemoglobin ≥ 9.0 g/dL;
  • PT/INR, aPTT ≤ 1.5 x ULN unless participant is receiving a stable dose of therapeutic anticoagulation;
  • Albumin ≥ 3.0 g/dL;
  • Creatinine clearance or eGFR ≥ 30 mL/min as estimated by the Cockcroft-Gault equation;
  • AST/ALT ≤ 2 x ULN. If documented liver metastases, then ≤ 5 x ULN;
  • Bilirubin ≤ 2 x ULN; or bilirubin ≤ 3 x ULN if due to Gilbert’s or Crigler-Najjar disease.
• Available representative tumor specimens in paraffin blocks (preferred) or ≥ 20 unstained slides, with an associated pathology report, obtained after last systemic anti-cancer therapy and within 60 days prior to the planned first dose of investigational product. If fewer than 20 unstained slides are available, a discussion with the Medical Monitor is required prior to enrollment. If an archived sample is not available, participant must have a tumor that is amenable to biopsy without unacceptable risk of a major procedural complication and consent to have a tumor biopsy. Tumor lesions used for biopsy should not be lesions used as RECIST 1.1 target lesions unless there are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion must be ≥ 2cm in longest diameter:
  • For the pembrolizumab combination therapy cohort:
  • A biopsy collected within 60 days of the planned first dose of investigational product while the participant is receiving pembrolizumab is acceptable.
• Women of childbearing potential (WOCBP) and fertile males with partners who are WOCBP must use highly effective contraception (per CTFG 2014) from first dose and through 90 days after final dose of investigational product.
• Willing and able to provide written informed consent and able to comply with all trial procedures.

• Disease that is suitable for local therapy administered with curative intent.
• Malignant disease other than the malignancy to be investigated in this trial within the last 5 years with the exception of basal or squamous cell carcinoma of the skin OR curatively treat in situ disease.
• Autoimmune disease requiring systemic treatment (e.g., with disease modifying agents, corticosteroids, or immunosuppressive drugs) in the past 2 years. Hormone replacement therapy (e.g., insulin, thyroxine, and replacement-dose hydrocortisone) is not considered systemic treatment.
• Active or prior paraneoplastic neurologic disorder of the central nervous system (CNS).
• Prior allograft.
• Clinically significant cardiovascular disease; e.g., cerebral vascular accident/stroke or myocardial infarction, within 6 months prior to the first dose of investigational product, unstable angina, congestive heart failure (New York Heart Association ≥ Class III), or unstable cardiac arrhythmia requiring medication.
• Presence of active, symptomatic, or untreated CNS metastasis; or CNS metastasis that requires local directed therapy or increasing doses of corticosteroids within the 2 weeks prior to the planned first dose of investigational product. Individuals with treated and/or asymptomatic CNS disease may be enrolled if neurologically stable over the prior 2 weeks (and after consultation with the Medical Monitor).
• HIV infection with an AIDS-defining  opportunistic infection within the past 12 months or with a CD4+ T cell count < 350/µL
• Hepatitis B surface antigen (HBsAg) positive OR anti-Hepatitis B core (anti-HBc) positive and HBV viral load above the lower limit of quantification.
• Hepatitis C antibody positive with HCV viral load greater than or equal to the lower limit of quantification.
• Infection requiring intravenous antibacterial, antiviral, or antifungal therapy within 2 weeks prior to the planned first dose of investigational product.
• Ongoing ≥ Grade 2 toxicity(ies) due to a previously administered anticancer agent with the following exceptions:
  • Grade 2 neuropathy or alopecia;
  • For the monotherapy cohorts: Grade 2 immune-related endocrinopathy attributed to a checkpoint inhibitor and controlled with hormone replacement alone.
• Treatment with biological agents (including monoclonal antibodies) within 28 days of the planned first dose of investigational product with the following exception:
  • For the pembrolizumab combination therapy cohort: Pembrolizumab treatment within 28 days of the planned first dose of investigational product.
• Treatment with radiation, chemotherapy or anticancer small molecule therapy within 14 days or 5 half-lives (whichever is longer) prior to the planned first dose of investigational product. Treatment with nitrosoureas or mitomycin C require a 42-day washout prior to the planned first dose of investigational product.
• Receipt of any investigational drug or device not otherwise specified above within 28 days or 5 half-lives (whichever is longer) prior to the planned first dose of investigational product.
• Pregnant or breastfeeding; negative pregnancy status in WOCBP must be confirmed by serum pregnancy test at Screening.
• History of ≥ Grade 3 infusion-related reaction associated with antibody administration; or:
  • For the monotherapy cohorts: Known allergy/intolerance to ATRC-101 or its excipients;
  • For the pembrolizumab combination therapy cohort: Known allergy/intolerance to ATRC-101, pembrolizumab, or their excipients.
• Major surgery or significant traumatic injury occurring within 28 days prior to the planned first dose of investigational product. If major surgery occurred > 28 days prior to Cycle 1-Day 1, individual must have recovered adequately from the toxicity and/or complications from the intervention prior to Cycle 1-Day 1.
• Prior treatment with ATRC-101.
• Intercurrent illness that is either life-threatening or of clinical significance such that it might limit compliance with trial requirements, or in the Investigator’s assessment would place the participant at an unacceptable risk for participation.
• Receipt of a live vaccine within 30 days of planned Cycle 1-Day 1. 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 inactivated flu vaccines and are allowed. Intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.

For the pembrolizumab combination therapy cohort ONLY:

• Experienced ≥ Grade 3 or higher immune related adverse events while on immunotherapy prior to enrollment.
• Have not recovered from ≥ Grade 2 immune related adverse events attributed to immunotherapy prior to enrollment.
• NSCLC with epidermal growth factor receptor (EGFR) or anaplastic lymphoma receptor tyrosine kinase (ALK) genomic tumor alterations.
• Isolated intracranial relapse.
• Interstitial lung disease or active, non-infectious pneumonitis.
• Signs and symptoms consistent with clinically significant, decreased pulmonary function: (1) blood saturation oxygen level (SpO2) < 90% at rest on room air; (2) dyspnea at rest (CTCAE ≥ Grade 3) or required supplemental oxygenation within 14 days prior to the planned first dose of investigational product.
• Ongoing immune-related toxicity or immune-related toxicity at any time requiring systemic corticosteroids.

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Patient must have histologically confirmed HER2-positive primary invasive breast carcinoma, as defined by the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) HER2 testing guideline focused update (Wolff et al, 2018) and determined by local testing.
• Patients hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) status must be known and will be determined by local testing. Patients with either hormone receptor-positive or hormone receptor-negative HER2-positive breast cancer are eligible.
• Patients must have clinical stage II and IIIa (T2-3/N0-2/M0) at diagnosis.
• Patients without nodal involvement (cN0) are eligible if T size ≥ 2.0 cm. 
• Patients with nodal involvement (cN1-2) are eligible if T size ≥ 1.5 cm.
• Patient must be willing and able (i.e., have no contraindication) to receive standard adjuvant therapy, consisting of HER2-directed therapy, radiation (if indicated) and endocrine therapy (if ER+) if achieving pCR at surgery.
• Patient with two separate invasive breast cancers (ipsilateral or bilateral) are eligible if both cancers are HER2-positive and at least one meets protocol eligibility (i.e., ≥ 1.5 cm if cN1-2; ≥ 2 cm if cN0) (neither tumor can be T4 or N3).
• Patients with multifocal or multicentric disease are eligible as long as all tumor foci that were tested for HER2 status at the local institution are HER2-positive, and at least one tumor focus meets eligibility criteria. 
• Patients with a history of other non-breast malignancies are eligible if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
• Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, and localized papillary or follicular thyroid cancer who have completed recommended treatment including surgery. Patients with any other cancers within the last 5 years are ineligible.
• Patents must have a left ventricular ejection fraction (LVEF) within normal institutional parameters (or > 50%).
• Patients must have a bilateral mammogram and diagnostic breast ultrasound (with or without breast magnetic resonance imaging [MRI]) performed at screening (within 42 days of registration).
• Baseline imaging of the ipsilateral axilla by ultrasound is mandatory. For subjects with axillary lymph node(s) suspicious on clinical exam or imaging, patient must be willing to have a needle aspiration or core biopsy to determine the presence of metastatic disease in the lymph nodes. A clip must be placed in the involved axillary lymph node.
• Women of childbearing potential and sexually active males must use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 7 months after the last dose of study treatment.
• Patient must be willing and able to sign informed consent.
• Leukocytes ≥ 3,000/mcL (obtained ≤ 28 days prior to protocol registration).
• Absolute neutrophil count ≥ 1,500/mcL (obtained ≤ 28 days prior to protocol registration).
• Platelets ≥ 100,000/mcL (obtained ≤ 28 days prior to protocol registration).
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained ≤ 28 days prior to protocol registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (obtained ≤ 28 days prior to protocol registration).
• Creatinine ≤ 1.5 x institutional ULN (obtained ≤ 28 days prior to protocol registration).
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Patient must not have a history of any prior (ipsilateral or contralateral) invasive breast cancer.
• One exception: a patient with a history of T1N0 triple negative breast cancer diagnosed more than 10 years earlier, who remains disease free is eligible.
• Patient must not have prior ipsilateral ductal breast carcinoma in situ (DCIS). Patients with prior lobular breast carcinoma in situ (LCIS), atypical hyperplasia, other high risk benign lesions or contralateral DCIS (without evidence of microinvasion) are eligible.
  • NOTE: Patients currently receiving endocrine therapy for prior contralateral DCIS are eligible.
  • Patient must not have stage IV (metastatic) breast cancer. 
• Staging studies (computed tomography [CT] chest/abdomen/pelvis and a bone scan or positron emission tomography [PET]-CT scan) are required for stage III disease or those with abnormal baseline liver function tests (LFTs), symptoms (e.g., new bone pain) or abnormal physical exam findings (National Comprehensive Cancer Network [NCCN] guidelines version [V]1.2019). 
• Patient must not have T4 and/or N3 disease, including inflammatory breast cancer.
• Patient must not have any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation or experimental therapy.
• Patients must not have > grade 1 peripheral neuropathy of any etiology.
• Patient must not have a concurrent serious medical condition that would preclude completion of study therapy. For example, uncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e., active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to registration, unstable angina, congestive heart failure (CHF) or serious cardiac arrhythmia requiring medication and other concurrent serious diseases that may interfere with planned treatment.
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive from the time of registration, while on study treatment, and until at least 7 months after the last dose of study treatment. All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy;
  • has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

• Diagnosis of chronic kidney disease (CKD) and active candidate on the kidney donor waitlist at the time of screening.
• Body mass index (BMI) ≤ 40 kg/m^2.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent.

For Participants in Cohort A

• Active candidates on the kidney waitlist with living donor.

For Participants in Cohort B

• Active candidates on the kidney waitlist with no living donor cleared for donation.

• Significant cardiac dysfunction.
• Known active, recurrent, or chronic infection.
• Active lupus or uncontrolled diabetes.
• Prior treatment with rituximab within 6 months from SAR650984 administration.
• Inadequate organ and bone marrow function at screening.
• Pregnant or breastfeeding women or women who intend to become pregnant during participation in the study.
• Known intolerance or hypersensitivity to any component of SAR650984 or premedications.
• Participants who are not suitable for participation as judged by the Investigator.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

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

• Children, below 18 years of age.

• Patients 18 years of age or older.
• Adults who have been admitted to the Mayo Clinic Inpatient Medical services at Mayo Clinic Hospital-Rochester within 30 days of discharge from a prior hospitalization at Mayo Clinic Hospital-Rochester. 
• Patients who are admitted as both inpatient and observation status will be eligible for participation in the study.

• Patients under 18 years of age.
• Patients who are admitted or readmitted to a hospital other than Mayo Clinic Hospital-Rochester will not be eligible.
• Patients not admitted to an inpatient Medicine service at Mayo Clinic Hospital-Rochester will not be eligible.

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

Eligibility last updated 8/30/22. Questions regarding updates should be directed to the study team contact.

• Patients scheduled for large-volume spinal taps