• Diagnosis of Alzheimer’s Dementia according to NIA-AA Criteria for dementia.
• MMSE ≤ 15.
• Cohen-Mansfield Agitation Inventory Nursing Home Version (CMAI) score of >5 on at least one item of aggression or a physical nonaggressive item that holds potentially dangerous consequences including hitting (including self), kicking, grabbing onto people, pushing, throwing things, biting, scratching, spitting, hurting self or other, tearing things or destroying property, making physical sexual advances, trying to get to a different place, intentional falling, screaming, making verbal sexual advances, and cursing or verbal aggression (items 1-11, 14, 15, 22-24).
• At least three failed pharmacological interventions from different drug classes (including antidepressants, antipsychotics, anticonvulsants, prazosin, and cannabinoids) at therapeutic doses (to be determined by clinical judgment) and duration of at least two weeks each to manage behavioral symptoms. These interventions may also include medications discontinued after 1 week due to tolerability concerns. Furthermore, medication trials that occur prior to admission to the hospital may count towards the three failed trials. The trials can be inpatient and/or outpatient. These trials can also be concurrent, such as using two medications from different classes for at least one week  at the same time (i.e., polypharmacy).
• Medically stable for safe administration of ECT verified by standard physical examination, urinalysis and serum chemistries.
• Comprehension of English language.
• Authorized legal representative able and willing to give informed consent.
• Age 55
  •89 years old (inclusive).

• Current diagnosis of co-morbid delirium, measured by the Confusion Assessment Method (CAM) and by clinical diagnosis.
• Diagnosis of Non-AD Dementia.
• Lifetime or current diagnosis of Schizophrenia, Bipolar Disorder or Schizoaffective Disorder.
• Active substance use disorder within past 6 months.
• Treatment with ECT or other neurostimulation therapies (e.g., TMS or vagal nerve stimulation) within the past 3 months.

• Adults aged 18 to 80 years, inclusive.
• Diagnosed with celiac disease based on positive serology (eg, tissue transglutaminase IgA antibody and/or deamidated gliadin peptide IgG) and intestinal histology consistent with ≥ Marsh Type II or with evidence of villous atrophy.
• Has HLA-DQ2.5 genotype (HLA-DQA1*05 and HLA-DQB1*02) (homozygotes or heterozygotes).
• Has followed a GFD for > 12 months immediately prior to study entry.
• Negative for tTG and negative or weak positive for DGP-IgA/IgG during screening.
• Male or female, and using at least 2 acceptable birth control methods or who are sterile or postmenopausal.
• Capable of understanding and complying with protocol requirements.
• Patient understands and has signed the informed consent form.

• Refractory celiac disease.
• Selective IgA deficiency.
• Positive for HLA-DQ8 (DQA1*03, DQB1*0302).
• Previous treatment with tolerance-inducing therapies for celiac disease.
• Known wheat allergy.
• Part B only: History of hyperacute or prolonged symptoms following gluten exposure.
• Uncontrolled or significant medical conditions (including active infections or chronic hepatitis) which, in the opinion of the Investigator, preclude participation.
• History of dermatitis herpetiformis.
• Pregnant or breastfeeding.

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

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

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

• The subject must consent to take precautionary measures to prevent Newcastle Disease Virus (NDV) transmission to humans and birds.
• Subjects must have histologic documentation of advanced solid tumor and received and have progressed, are refractory, or are intolerant to standard therapy for the specific tumor type. All subjects are required to have had at least one prior line of treatment in the recurrent or metastatic setting.
• Subjects must have at least 1 measurable lesion.
• All subjects must consent to provide tumor tissue for correlative studies.
• ECOG performance status of 0 to 1.
• Adequate organ function.
• Use of highly effective contraception (females) or male condom plus spermicide (males).

• Rapidly progressing disease defined as a subject that cannot tolerate a break of at least 8 weeks from systemic anticancer therapy. 
• Primary central nervous system (CNS) disease is excluded.
• Subjects who have received prior immunotherapy will require varying washout times prior to the first dose of MEDI5395.
• Unresolved toxicities from prior anticancer therapy.
• History of severe allergic reactions to any of the study drug components.
• Infectious disease exclusions including tuberculosis, Human immunodeficiency virus (HIV), hepatitis A, B or C, active bacterial, fungal or viral infections plus receipt of live attenuated vaccine prior to first dose of MEDI5395.
• (NOTE: Subjects with hepatitis B/C with undetectable virus load and are on medications may be permitted). 
• Any conditions requiring use of any systemic immunosuppressant including systemic corticosteroids, methotrexate, azathioprine, tumor necrosis factor (TNF) inhibitor, and/or interleukin 6 (IL-6) blockers.
• Active autoimmune disease or chronic inflammatory condition (Exceptions include vitiligo, alopecia, hypothyroidism on stable treatment, diverticulosis, controlled celiac disease and chronic skin conditions not requiring systemic therapy).
• Active acquired immune-deficiency states.
• Subjects who are regularly exposed to poultry or birds.
• Current active hepatitis or biliary disease (except for Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease).
• Clinically significant pulmonary disease and cardiac disease.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

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

Eligibility last updated 12/20/22. Questions regarding updates should be directed to the study team contact.

• Signed informed consent.
• Either of the following:
  • Completed the full treatment period of the lead-in trial (ZP1848-17111), regardless of treatment adherence; OR
  • Completed the Phase 2 trial (ZP1848-15073).

• Withdrew consent from lead-in or Phase 2 trial.
• Any condition, disease, or circumstance that in the Investigator's opinion would put the patient at any undue risk, prevent completion of the trial, or confounds planned assessments of the trial.
• Use of GLP-1, GLP-2, human growth hormone (HGH), dipeptidyl peptidase-4 (DPP-4) inhibitors, citrulline, somatostatin, or analogs thereof within 3 months.
  • Note: Prior glepaglutide trial drug is allowed.
• Females of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant, or are not using highly effective contraceptive methods. Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• An employee of the sponsor or Investigator or otherwise dependent on them.

Additional Exclusion Criteria Applicable for Patients from the Phase 2:

Trial Patients from the ZP1848-15073 trial (Phase 2 trial) must be excluded from this trial if any of the following criteria are met:

• Not having a diagnosis of SBS defined as remaining small bowel in continuity of estimated less than 200 cm [equal to 79 inches] with the latest intestinal resection being at least 6 months prior to Screening;
• Restorative surgery planned in the trial period;
• SBS-related hospitalizations within 30 days prior to screening;
• Not maintaining a stable PS volume for at least 2 weeks.
  • Note: PS volume is considered stable if both of the criteria below are fulfilled:
  • Actual PS usage (volume and content) matches prescribed PS (± 10% deviation in volume is acceptable); and
  • Urine volume is on average ≥ 1 L per day and ≤ 2.5 L per day.
• Not willing to adhere to an individual pre-defined drinking menu during 48-hours measurement periods;
• Not having a colonoscopy performed during Screening (for patients with remnant colon).
  • Note: The results of the colonoscopy must not give rise to any safety concerns. A colonoscopy performed within 6 months prior to Screening and not giving rise to any safety concerns is accepted. For patients with a remnant colon, which is not connected to the passage of foods and is thereby dormant, a computerized tomography (CT) scan or magnetic resonance imaging (MRI) will suffice at the discretion of the Investigator.
• Not being able to separate stool and urine during the 48-hours measurement periods;
• Any history of colon cancer;
• History of any other cancers (except margin-free resected cutaneous basal or squamous cell carcinoma or adequately treated in situ cervical cancer) unless disease-free state for at least 5 years;
• Poorly controlled inflammatory bowel disease (IBD) that is moderately or severely active or having a fistula interfering with the trial assessments;
• Bowel obstruction or recent history of sub-ileal events;
• Human immunodeficiency virus (HIV) positive, acute liver disease, or unstable chronic liver disease;
• Cardiac disease defined as: decompensated heart failure (New York Heart Association [NYHA] Class III-IV), unstable angina pectoris, and/or myocardial infarction within the last 6 months prior to Screening;
• Clinically significant abnormal screening ECG as judged by the Investigator;
• Repeated (2 or more consecutive measurements) systolic blood pressure measurements >180 mm Hg;
• Systemic immunosuppressive therapy that has been introduced or has been unstable within 3 months prior to Screening;
• Unstable biological therapy (e.g., TNF-α (anti-tumor necrosis factor), natalizumab, etc.), including significant changes in doses or switch of drug within 6 months prior to Screening;
• Unstable doses within 2 weeks prior to screening:
  • Antimotility drugs; e.g., loperamide, diphenoxylate, codeine or other opiates;
  • H2 antagonists;
  • Anti-diarrheal agents;
  • Bile acid sequestering agents;
  • Oral glutamine;
  • Proton pump inhibitors;
  • Diuretics;
  • Systemic antibiotics or antibiotics affecting the gastrointestinal tract;
  • Oral rehydration fluids.
• Estimated creatinine clearance (CLcr; by the Cockcroft-Gault formula) < 30 mL/min.;
• Hepatic impairment defined as:
  • Total bilirubin ≥ 2 × the upper limit of normal (ULN); or
  • Aspartate aminotransferase (AST) ≥ 5 × ULN; or
  • Alanine aminotransferase (ALT) ≥ 5 × ULN.

• Adult patients with brain metastases, for whom gamma knife radiosurgery recommended.

• Patients unable to tolerate/obtain MRI brain.

Screening Period

• Signed written informed consent in accordance to ICH-GCP and national/local regulation before any protocol-related procedures that are not part of normal patient care.
• Female patients ≥ 18 years of age.
• Histologically confirmed high grade, stage IIIC or stage IV (FIGO staging) serous ovarian, fallopian or primary peritoneal carcinoma with abnormal CA-125 at diagnosis.
• Patients who have undergone primary debulking surgery or interval debulking surgery and completed a total of at least 5 cycles of taxane-platinum combination.
  • Note: patients may have received concurrent or maintenance bevacizumab or a PARP inhibitor.
• Patients must have achieved a complete response to therapy, as demonstrated by no residual disease on most recent CT scan and normal CA-125 not increasing by both the following: > 25% from nadir AND ≥ 10 UI/mL from nadir.
• Patient who remains disease free at least 6 months from last prior dose of cytotoxic chemotherapy (maintenance therapy with bevacizumab or a PARP inhibitor is allowed).
• Available tumor tissue, banked from previous abdominal debulking surgery and/or from a core needle biopsy performed at diagnosis if the patient received neoadjuvant chemotherapy, and peripheral blood samples for exome and transcriptome sequencing.

Treatment Period

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at treatment period initiation.
• Patients who have developed an asymptomatic relapse as defined by:
  • Cohort A: CA-125 ≥ 2 times ULN on 2 occasions at least 1 week apart (GCIG criteria) or low volume radiological disease and CA-125 > ULN. Low volume radiological disease is defined as radiologically visible disease excluding intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage;
  • Cohort B: patient asymptomatic with measurable disease, excluding intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage, whatever serum CA-125 level and for whom further treatment is not planned within 2 months.
  • Longest diameter on CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 cm in short axis for nodal lesions.
• Adequate hematological, hepatic and renal functions:
  • Hemoglobin ≥ 9.0 g/dL;
  • Neutrophils count ≥ 1.5 x10^9 /L;
  • Lymphocytes count ≥ 0.9 x10^9 /L;
  • Platelets count ≥ 100 x10^9 /L;
  • Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert’s syndrome);
  • Aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Calculated creatinine clearance ≤ 45 mL/min using the Cockroft & Gault formula or ≥ 45 mL/min/1.73m² using other methods.
• Patients who received standard maintenance therapy will stop before initiation of TG4050 administration. A free-interval of at least 30 days will be respected before first dosing of TG4050 except for PARP inhibitor (at least 14 days).

Screening Period

• Patient having received any cancer immunotherapy including cancer vaccines, any antibody/drug targeting T cell co-regulatory proteins such as anti-PD1, anti-PDL1 or anti-CTLA-4.
• Patients with other active malignancy ≤ 3 years prior to registration except non-melanoma skin cancer, stage 0 in situ carcinoma and recent early stage papillary thyroid cancer. If there is an history of prior malignancy, patient must not be receiving other specific treatment for their cancer.
• Patient post-organ transplantation, including allogeneic stem cell or bone marrow transplantation. History of blood transfusion within 3 weeks prior to study entry visit.
• Known history of positive testing for Human Immunodeficiency Virus (HIV) or known AIDS (Acquired Immune Deficiency Syndrome).
• Any known allergy or reaction to eggs or attributed to compounds of similar chemical or biological composition to therapeutic vaccines/immunotherapeutic products.
• Positive serology for Hepatis C Virus (HCV) or positive serum Hepatitis B surface antigen (HBsAg) within 3 months prior to or at study entry (tests required).

Treatment Period

• Measurable disease associated with the appearance of symptoms justifying initiation of further treatment.
• Major surgery within 4 weeks prior to treatment start.
• Treatment with another investigational agent within 30 days prior to TG4050 treatment initiation.
• Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to TG4050 treatment initiation planned date, with the exception of patients with adrenal insufficiency who may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
• Vaccination for the prevention of infectious diseases with a live vaccine during the four-week period prior to TG4050 treatment initiation planned date. Furthermore, patients should not receive any live vaccine during the period of study treatment administration.
• Patient with any underlying medical condition, that in the opinion of the investigator, could make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety or toxicity of the study treatment.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social circumstances that could limit compliance with study requirements.
• History of myocardial infarction ≤ 6 months.

Eligibility last updated 4/20/22. Questions regarding updates should be directed to the study team contact.

• 22- 65 years of age.
• Current diagnosis of T2D.
• History of T2D for at least 3 years and less than or equal to 10 years.
• HbA1C of 7.5-10.0%, inclusive.
• BMI 24-40 kg/m^2, inclusive.
• On two to three non-insulin glucose lowering mediations, with one at maximum tolerated dose and another at half-maximum dose at least, with no changes in medication for at least 12 weeks prior to baseline visit prior to baseline visit.
• History of failed attempt to reach glycemic goal by lifestyle modifications.
• Weight stability (defined as a < 5% change in body weight) for at least 12 weeks prior to the screening visit.
• Agree not to donate blood during participation in the study.
• Able to comply with study requirements and understand and sign the Informed Consent Form.
• Women of childbearing potential must be using an acceptable method of contraception throughout the study.
• Willing and able to use CGM for the duration of the study and comply with study visits and study tasks as required per protocol.
• Proof of COVID 19 vaccination.

• Diagnosed with type 1 diabetes.
• History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
• Probable insulin production failure, defined as overnight fasting C-peptide serum <1 ng/mL (333pmol/l).
• Previous use of any types of insulin for > 1 month (at any time, except for treatment of gestational diabetes) in last 2 years.
• Current use of insulin.
• Hypoglycemia unawareness.
• History of ≥1 severe hypoglycemia episode (defined by needing for third-party assistance) in past 6 months from the screening visit.
• Known autoimmune disease, as evidenced by a positive anti-glutamic acid decarboxylase (GAD) test, including but not limited to celiac disease, or pre-existing symptoms of systemic lupus erythematosus, scleroderma or other autoimmune connective tissue disorder. (Participants with adequately controlled primary hypothyroidism may be included).
• Previous GI surgery that has changed GI anatomy or could limit treatment of the duodenum, such as Billroth 2, Roux-en-Y gastric bypass, gastric band or other similar procedures or conditions.
• Known history of a structural or functional disorder of the upper GI tract that may impede passage of the device through the upper GI tract or increase risk of tissue damage during an endoscopic procedure, including esophagitis, stricture/stenosis, varices, diverticula, or other disorder of the esophagus, stomach and duodenum.
• Active H. pylori infection (Participants with active H. pylori may continue with the screening process if they are treated with an appropriate antibiotic regimen).
• History of, or gastrointestinal symptoms suggestive of gastroparesis.
• Acute gastrointestinal illness in the previous 7 days.
• Known history of irritable bowel syndrome, radiation enteritis or other inflammatory bowel disease, such as Crohn's disease and Celiac disease.
• History of chronic or acute pancreatitis.
• Known active hepatitis or active liver disease other than NASH/NAFLD.
• Alcoholic liver disease, as indicated by ANI > 0.
• Current use of anticoagulation therapy (such as warfarin) that cannot be discontinued for 7 days before and 14 days after the procedure.
• Current use of P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) that cannot be discontinued for 14 days before and 14 days after the procedure.
• Unable to discontinue non-steroidal anti-inflammatory drugs (NSAIDs) during treatment through 4 weeks following the procedure. Use of acetaminophen and low dose aspirin is allowed.
• Use of systemic glucocorticoids (excluding topical or ophthalmic application or inhaled forms) for more than 10 consecutive days within 12 weeks prior to the baseline visit.
• Use of drugs known to affect GI motility (e.g., Metoclopramide).
• Use of weight loss medications such as Meridia, Xenical, Phentermine or over-the-counter weight loss medications (prescription medication).
• Currently taking, or unable to stop taking dietary supplements or herbal agents, including vitamin C or multivitamins containing vitamin C at > 500 mg per day, multivitamins containing biotin (vitamin B7), and supplements for hair, skin, and nail growth. Multivitamins not containing biotin are permitted.
• Persistent anemia, defined as hemoglobin < 10 g/dL.
• Known history of hemoglobinopathy.
• Known history of blood donation or transfusion within 3 months prior to the Screening Visit.
• Known history of cardiac arrythmia.
• Significant cardiovascular disease, including known history of valvular disease, or myocardial infarction, heart failure, transient ischemic attack, or stroke within 6 months prior to the Screening Visit.
• Estimated glomerular filtration rate (eGFR) ≤ 60 ml/min/1.73m^2 (estimated by MDRD).
• Known immunocompromised status, including but not limited to individuals who have undergone organ transplantation, chemotherapy, or radiotherapy within the past 12 months, who have clinically significant leukopenia, who are positive for the human immunodeficiency virus (HIV) or whose immune status makes the participant a poor candidate for clinical trial participation in the opinion of the investigator.
• History of secondary hypothyroidism or inadequately controlled primary hypothyroidism (TSH value outside the normal range at screening).
• With any implanted electronic devices or duodenal metallic implants
• Not a candidate for upper GI endoscopy or general anesthesia.
• Active illicit substance abuse or alcoholism (> 2 drinks/day regularly).
• Active malignancy within the last 5 years (excluding non-melanoma skin cancers).
• Women breastfeeding.
• Participating in another ongoing clinical trial of an investigational drug or device.
• Any other mental or physical condition which, in the opinion of the study investigator, makes the participant a poor candidate for clinical trial participation.
• Critically ill or has a life expectancy < 3 years.
• Additional exclusion criteria to be confirmed during the screening process:
  • HbA1c < 7.5% or > 10% at baseline visit;
  • Any severe hypoglycemic event since the screening visit;
  • CGM readings < 54 mg/dl in more than 1% of time by CGM since the screening visit;
  • CGM readings > 360 mg/dL in more than 1% of time.
  • Mean of 3 separate blood pressure measurements > 180 mmHg (systolic) or > 100 mmHg (diastolic).
• Women of child-bearing potential with a positive urine pregnancy test at baseline visit.
• LA Grade C or greater esophagitis on endoscopy.
• Abnormalities of the GI tract preventing endoscopic access to the duodenum.
• Anatomic abnormalities in the duodenum that would preclude the completion of the treatment procedure, including tortuous anatomy.
• Endoscopic observation of upper gastrointestinal abnormality such as ulcers, polyps, varices, strictures, congenital or intestinal telangiectasia.
• Any other anatomical or endoscopic abnormalities/characteristics that, in the opinion of the investigator, would preclude safe use of the investigational device or procedure.

• Men who are currently receiving androgen deprivation therapy (ADT) for the treatment of prostate cancer. ADT is defined by a history of orchiectomy, or ongoing usage of gonadotropin-releasing hormone agonists or antagonists.
• Men receiving next generation androgen axis inhibitor therapies including abiraterone, enzalutamide, apalutamide, and darolutamide are eligible.
• Patients must be on a stable dose of all hormone-directed therapies for at least 28 days prior to registration and must not be planning to discontinue this therapy for at least 42 days following registration.
• Patients receiving radiation therapy during the study period are eligible.
• Eligible patient must have bothersome hot flashes for ≥ 14 days prior to registration, defined by an occurrence of ≥ 28 times per week and of sufficient severity to cause the patient to seek therapeutic intervention.
• Life expectancy of greater than 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status
  •0, 1, or 2.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English.

• No current use or future planned use of any of the following agents during the study period: drugs that are not Food and Drug Administration (FDA) approved for use in humans, androgens, estrogens, progesterone analogs, gabapentin, selective serotonin reuptake inhibitor (SSRI)/serotonin and norepinephrine reuptake inhibitor (SNRI) anti-depressants, cholinergic agonists, cholinesterase inhibitors, or complementary/alternative medicine taken for the purpose of managing hot flashes. Prior use of these agents is permitted as long as they are discontinued before registration.
• No current or prior use of oxybutynin.
• Patients with a history of any of the following contraindications to oxybutynin are not eligible:
  • gastroparesis or gastrointestinal obstructive disorders;
  • significant gastric reflux symptoms not controlled by medication; ulcerative colitis;
  • narrow-angle glaucoma;
  • urinary retention requiring indwelling or intermittent self-catheterization within the prior 6 months;
  • hypersensitivity to oxybutynin or any other components of the product; current uncontrolled hyperthyroidism;
  • uncontrolled coronary artery disease or a history of myocardial infarction within the prior 12 months;
  • New York Heart Association (NYHA) class II-IV congestive heart failure;
  • symptomatic cardiac arrhythmias;
  • current uncontrolled hypertension;
  • myasthenia gravis; or
  • dementia.

Eligibility last updated 11/22/21. Questions regarding updates should be directed to the study team contact.

• Critically ill adult (>18 years old) patients and expected to have >48-hour ICU stay.
• Functional GI tract (able to tolerate oral diet or tube feeding).

• Premorbid known immunosuppression over 1 month duration (due to medications including chronic steroids, TNF-alpha inhibitors, monoclonal antibodies, immunosuppressive antimetabolites, etc.).
• Compromised gut integrity (bowel resection, GI malignancy, GI bleed, inflammatory bowel disease, intestinal obstruction, intra-abdominal hypertension, intestinal ischemia/reperfusion injury or secondary ileus).
• Dairy intolerance or milk allergy.
• Extremely poor prognosis and not expected to survive the treatment period.
• Goals of care change to comfort care.
• Pregnant patients.

Patients:

• Patients ≥ 21  years of age hospitalized for non-elective reasons for complications of cirrhosis.
• Adult caregiver and the patient living in the same house or the caregiver may include a consistent person involved in and/or familiar with the patient’s health and routine subject to investigator approval.
• Able to complete the Patient Buddy training and evaluation.
• Discharged home from the hospital.
• Patients who have the discharge hospital as a primary hospital base.

Caregivers:

• Living in same dwelling as patient for the last ≥ 1 year.
• Able to complete the Patient Buddy training and evaluation.
• Familiar with the patient’s routines.

Patients:

• Elective hospitalization.
• Lack of an adult caregiver.
• Active substance abuse within 1 month of the hospitalization (alcohol use is acceptable provided the patient does not have alcoholic hepatitis during this admission or < 1 month prior to admission).
• Unable to perform training or give consent.
• Patients discharged to hospice, nursing home or extended care facilities.

Caregivers:

• Unable or unwilling to train or adhere to study guidelines.
• Unfamiliar with the patient routines or not in the same house as the patient.

Eligibility last updated 6/8/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 2/9/23. Questions regarding updates should be directed to the study team contact.

• Non-treatment seeking male or females ages 18 to 65 years, inclusive.
• DSM-5 diagnosis of cocaine use disorder in sustained remission as confirmed by the PI’s review of the medical record.
• Are motivated to abstain from cocaine use during the period of the study, as evidenced both by the judgment of the Investigator or designee and by compliance with the requirement to make regular clinic visits.
• In the opinion of the PI, be in good general health as determined by medical and psychiatric history, general clinical examination, vital signs, and laboratory tests.
• Have provided written informed consent. Subjects should be cooperative, willing and able to participate and adhere to the protocol requirements.
• Have hematology, chemistry, kidney and liver function laboratory tests that are within (+/- 10%) of the current Mayo Clinic standardized normal values.
• Show a baseline EKG that demonstrates normal sinus rhythm and conduction without clinically significant abnormalities or arrhythmias.
• Are willing to return to research area for follow-up.

• They show detectable pre-existing immunity to the AAV8 capsid as measured by AAV8 transduction inhibition and AAV8 total antibodies.
• Evidence of HIV or hepatitis of any etiology.
• Creatinine ≥ 1.5 mg/dL.
• Any disease or mental health condition at the physician’s discretion that would prevent the subject from fully complying with the requirements of the study. The physician may exclude subjects with active alcohol abuse, other substance abuse or positive urine toxicology screen for substances of abuse.
• Pregnant &/or lactating. All lactating women will be excluded from study participation. Women of child-bearing potential must have a negative pregnancy test performed at screening visit, agree to use birth control throughout the study period, refrain from getting pregnant within the study period and consent to pregnancy testing throughout the study period. Men must agree to use barrier methods of birth control and refrain from fathering children within the next year.
• Morbid obesity (BM > 40).

• Must have a documented eligible invasive and/or severe fungal disease that is refractory or intolerant to Standard-of-Care treatment. A summary of eligible fungal diseases is listed below:
  • Acute or chronic invasive candidiasis, including candidemia;
  • Acute or chronic severe mucocutaneous candidiasis, including:
  • Esophageal candidiasis, Oropharyngeal candidiasis, Chronic mucocutaneous candidiasis, Vulvovaginal candidiasis;
  • Disseminated/invasive dimorphic fungi: Coccidioidomycosis, Histoplasmosis, Blastomycosis;
  • Chronic Pulmonary Aspergillosis;
  • Allergic Bronchopulmonary Aspergillosis;
  • Invasive Pulmonary Aspergillosis;
  • Other emerging fungi including yeasts and molds (e.g., saccharomycetes, scopulariopsis).
• Be able to tolerate medication orally or through a nasogastric (NG) tube or  percutaneous endoscopic gastrostomy (PEG) tube.
• Be able to understand and sign a written informed consent form (ICF), which must be obtained prior to treatment and any study-related procedures.
• Be able to understand and sign a consent or authorization form which shall permit the use, disclosure and transfer of the subject's personal health information. (e.g., in  the U.S. HIPAA Authorization form). 
• Be able to understand and follow all study-related procedures including study drug  administration.  
• Agree to use a medically acceptable method of contraception while receiving  protocol-assigned product.  

• An invasive fungal disease with CNS involvement.
• Subject has an inappropriately controlled fungal disease source (e.g., persistent  catheters that cannot be removed and are likely the source of infection).
• Subject is hemodynamically unstable, requiring vasopressor medication for blood  pressure support.  
• A life expectancy < 30 days.
• Subject with abnormal liver test parameters: aspartate aminotransferase (AST), alanine  aminotransferase (ALT) > 10 x the upper limit of normal (ULN), and/or total bilirubin > 5 x ULN.
• Subject is pregnant or lactating.
• Subject has used an investigational drug within 30 days prior to the baseline visit.

Eligibility last updated 9/13/21. Questions regarding updates should be directed to the study team contact.

• Patients must be 5 to 60 years of age at the time of enrollment
• Patients with newly diagnosed untreated histologically confirmed classic Hodgkin lymphoma (cHL) (nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified [NOS]) with stage I or II disease
• Patients must have bidimensionally measurable disease (at least one lesion with longest diameter >= 1.5 cm)
• Patients must have a whole body or limited whole body PET scan performed within 42 days prior to enrollment. PET-CT is strongly preferred. PET-MRI allowed if intravenous contrast enhanced CT is also obtained
• Pediatric patients (age 5-17 years) must have an upright posteroanterior (PA) chest X-ray (CXR) for assessment of bulky mediastinal disease. Adult patients must have either a CXR or CT chest
• Patients >= 18 years must have a performance status corresponding to Zubrod scores of 0, 1 or 2
• Patients =< 17 years of age must have a Lansky performance score of >= 50

• Pediatric patients (age 5-17 years): A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):

  • 2 to < 6 years (age): 0.8 mg/dL (male), 0.8 mg/dL (female)
  • 6 to < 10 years (age): 1 mg/dL (male), 1 mg/dL (female)
  • 10 to < 13 years (age): 1.2 mg/dL (male), 1.2 mg/dL (female)
  • 13 to < 16 years (age): 1.5 mg/dL (male), 1.4 mg/dL (female)
  • >= 16 years (age): 1.7 mg/dL (male), 1.4 mg/dL (female) OR a 24 hour urine creatinine clearance >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR a glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (within 7 days prior to enrollment). GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)
  • Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility
• For adult patients (age 18 years or older) (within 7 days prior to enrollment): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight

• Total bilirubin =< 2 x upper limit of normal (ULN) (within 7 days prior to enrollment)

  • Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome

• Aspartate aminotransferase (AST) =< 3 x ULN (within 7 days prior to enrollment)

  • Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome

• Alanine aminotransferase (ALT) =< 3 x ULN (within 7 days prior to enrollment)

  • Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile duct syndrome
• Shortening fraction of >= 27% by echocardiogram (ECHO), multigated acquisition scan (MUGA), or functional cardiac imaging scan (within 7 days prior to enrollment) or ejection fraction of >= 50% by radionuclide angiogram, ECHO, MUGA, or cardiac imaging scan (within 7 days prior to enrollment)
• Diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted value as corrected for hemoglobin by pulmonary function test (PFT) (within 7 days prior to enrollment). If unable to obtain PFTs, the criterion is: a pulse oximetry reading of > 92% on room air
• Known 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

• Patients with nodular lymphocyte predominant Hodgkin lymphoma
• Patients with a history of active interstitial pneumonitis or interstitial lung disease
• Patients with a diagnosis of inherited or acquired immunodeficiency that is poorly controlled or requiring active medications, such as primary immunodeficiency syndromes or organ transplant recipients
• Patients with any known uncontrolled intercurrent illness that would jeopardize the patient's safety such as infection, autoimmune conditions, cardiac arrhythmias, angina pectoris, and gastrointestinal disorders affecting swallowing and/or absorption of pills

• Patients with a condition requiring systemic treatment with either corticosteroids (defined as equivalent to > 10 mg daily prednisone for patients >= 18 years or > 0.5 mg/kg [up to 10 mg/day] for patients < 18 years) or other immunosuppressive medications within 14 days prior to enrollment

  • Note: Replacement therapy such as thyroxine, insulin, or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment. Inhaled or topical steroids, and adrenal replacement doses (=< 10 mg daily for patients >= 18 years or =< 0.5 mg/kg [up to 10 mg/day] prednisone equivalents) are permitted in the absence of active autoimmune disease
  • Note: Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but must be discontinued by cycle 1, day 1
• Patients with peripheral neuropathy > grade 1 at the time of enrollment or patients with known Charcot-Marie-Tooth syndrome
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Administration of prior chemotherapy, radiation, or antibody-based treatment for cHL
• Prior solid organ transplant
• Prior allogeneic stem cell transplantation
• Live vaccine within 30 days prior to planned day 1 of protocol therapy (e.g., measles, mumps, rubella, varicella, yellow fever, rabies, bacillus calmette guerin [BCG], oral polio vaccine, and oral typhoid). Administration of messenger ribonucleic acid (mRNA) vaccines are permitted
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test within 28 days prior to enrollment is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last treatment

• Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study drug therapy. Following therapy, patients will be advised to use contraception as per institutional practice or as listed below for investigational agents, whichever is longer

  • Men and women of childbearing potential must continue contraception for a period of 6 months after last dose of brentuximab vedotin
  • Women of child-bearing potential (WOCBP) must continue contraception for a period of at least 5 months after the last dose of nivolumab
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

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

Eligibility last updated 8/1/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 4 years.
• Able to use computer for assessment battery.
• Receiving cranial photon- or proton-based radiation for primary central nervous system malignancy.
• Histological or radiologic confirmation of intracranial disease.
• ECOG Performance Status (PS) 0-2, Karnofsky PS 60-100, or Lansky/Play PS for Children 60-100.
• Ability to complete clinical quality of life questionnaire(s) by themselves or with assistance.
• Demonstrates the capacity to sign informed consent.
• Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study, IRB number 15-000136*, **
  • * Patients do not need to agree to Registry blood draw.
  • **Patients at Mayo Clinic  Florida and Arizona can be enrolled without concurrent Registry consent.   

• Patients with WHO Grade IV astrocytoma or glioblastoma tumors.
  • Note: A patient with Grade IV tumors of other histology can participate in the study if they meet all other criteria.
  • Note: Diffuse Astrocytomas with molecular  features of glioblastoma are acceptable on study
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,  symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Any prior intracranial radiation.
• Patients receiving Gamma Knife radiosurgery.

Eligibility last updated 8/19/22. Questions regarding updates should be directed to the study team contact.

• STEP 1 REGISTRATION
• Tumor tissue must be available for submission for central pathology review
• Documentation from the enrolling site confirming the presence of IDH mutation and 1p/19q status; the provided information must document assays performed in clinical laboratory improvement amendments (CLIA)-approved laboratories
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 60 days prior to registration
  • Imaging of the brain within 60 days prior to registration
• Only English speaking patients are eligible to participate as the cognitive and quality of life assessments are available only in English
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Karnofsky performance status of >= 70 within 60 days prior to registration
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
• Platelets >= 100,000 cells/mm^3
• Hemoglobin >= 10.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)
• Bilirubin =< 1.5 upper limit of normal (ULN)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
• CD4 lymphocyte count is highly encouraged
• Women of childbearing age must have a negative serum pregnancy test within 14 days prior to registration
• Post-operative magnetic resonance (MR) imaging must be obtained for radiation therapy planning; enrolling sites are highly encouraged to obtain thin-slice volumetric fluid attenuated inversion recovery (FLAIR) and T1 post contrast sequences for planning purposes
• STEP 2 REGISTRATION
• The following baseline neurocognitive assessments must be completed and uploaded within 27 calendar days prior to step 2 registration: HVLT-R, TMT, and COWA
  • NOTE: Completed baseline neurocognitive assessments can be uploaded at the time of step 1 registration
• The following baseline patient reported outcome assessments must be completed and uploaded within 27 calendar days prior to Step 2 registration: MDASI-BT, LASA QOL, WPAI
• Financial clearance for proton therapy treatment within 30 days following step 1 registration
• Centrally reviewed histologically proven diagnosis of supratentorial, Word Health Organization (WHO) grade II or III astrocytoma, oligodendroglioma or oligoastrocytoma; tissue must be submitted x calendar days after step 1 registration
• Documentation must be uploaded within 15 business days and will be verified by the translational/pathology study co-chairs within 5 business days after receiving the upload; the documentation should demonstrate 1) evaluation of known IDH1 and IDH2 mutational hotspots (sequencing is encouraged) evaluation of chromosomes 1p and 19q copy number utilizing either fluorescence in situ hybridization (FISH) or other suitable assay

• Definitive clinical or radiologic evidence of metastatic disease; if applicable
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity or cervix are permissible)
• Prior cranial radiotherapy or radiotherapy to the head and neck where potential field overlaps would exist
• Prior chemotherapy or radiotherapy for any brain tumor
• Histologic diagnosis of glioblastoma (WHO grade IV) or pilocytic astrocytoma (WHO grade I)
• Definitive evidence of multifocal disease
• Planned use of cytotoxic chemotherapy during radiation (only adjuvant temozolomide therapy will be used on this protocol)
• Patients with infra-tentorial tumors are not eligible
• Prior history of neurologic or psychiatric disease believed to impact cognitive function
• The use of memantine during or following radiation is NOT allowed
• Severe, active co-morbidity defined as follows:
  • Unstable angina or congestive heart failure requiring hospitalization within 6 months prior to enrollment
  • Transmural myocardial infarction within the last 6 months prior to step 2 registration; evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 28 days prior to step 2 registration (Note: EKG to be performed only if clinical suspicion of cardiac issue)
  • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
  • Serious and inadequately controlled arrhythmia at step 2 registration
  • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
  • Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter; acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol
  • Any other severe immunocompromised condition
  • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
  • End-stage renal disease (i.e., on dialysis or dialysis has been recommended)
  • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
• Inability to undergo MRI with and without contrast (e.g. claustrophobia, non-MRI compatible implant or foreign body, gadolinium allergy or renal dysfunction preventing the patient from receiving gadolinium- institutional guidelines should be used to determine if patients are at risk for renal dysfunction); note that patients with severe claustrophobia are permitted on this study if they are willing and able to undergo MRI with adequate sedation or anesthesia

Eligibility last updated 1/23/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Body weight > 30 kg.
• Primary non small cell lung cancer treated previously on PACIFIC regimen (concurrent chemoradiation followed by durvalumab for stage III lung cancer).
• Progression during duvalumab administration or within 6 months after completion of final durvalumab infusion.
• Extracranial lesion > 4 cm amenable to grid therapy.
• Patients with brain metastases are permitted to enroll.
• Patients with polymetastatic disease are permitted to enroll.
• Patients with local recurrence are permitted to enroll.
• Patients who do not have rapid polymetastatic progression (at the discretion of the enrolling physician).
• Patients who have not had SBRT within 1 month of enrolment.
• Patients may receive conventional palliative radiation to other symptomatic metastatic disease.
• ECOG Performance Status (Dronca, Liu, et al.) 0-2.
• The following laboratory values obtained ≤15 days prior to registration:
  • Hemoglobin ≥ 9.0 g/dL;H
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ULN if total bilirubin is > 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Creatinine OR glomerular filtration rate (GFR) ≤ 1.5 x ULN; OR
  • GFR > 60 mL/min for patients with creatinine > 1.5 x ULN.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Persons able to become pregnant OR able to father a child must be willing to use an adequate method of contraception while on treatment and for 120 days after last treatment.
• Life expectancy ≥ 12 weeks.
• Provide written informed consent..
• Willingness to provide mandatory blood specimens for correlative research.
• Willing to return to Mayo Clinic for follow-up (during the Active Monitoring Phase of the study).

• < 18 years of age.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential OR able to father a child who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Active autoimmune disease requiring systemic treatment, documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
• NOTE: Exceptions are allowed for:
  • Vitiligo;
  • Resolved childhood asthma/atopy;
  • Intermittent use of bronchodilators or inhaled steroids;
  • Daily steroids at dose of ≤10mg of prednisone (or equivalent);
  • Local steroid injections;
  • Stable hypothyroidism on replacement therapy;
  • Stable diabetes mellitus on non-insulin therapy;
  • Sjögren’s syndrome.
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection requiring systemic therapy;
  • Interstitial lung disease;
  • Serious, chronic gastrointestinal conditions associated with diarrhea (e.g., Crohn’s disease or others);
  • Known active hepatitis B (i.e., known positive HBV surface antigen (HBsAg) reactive);
  • Known active hepatitis C (i.e., positive for HCV RNA detected by PCR);
  • Known active tuberculosis (TB);
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Unstable cardiac arrhythmia; or
  • Psychiatric illness/social situations that would limit compliance with study requirements (e.g., substance abuse).
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Hypersensitivity to durvalumab or any of its excipients.
• Previous adverse event attributed to durvalumab or other PD-1 or PD-L1 directed therapy that led to drug discontinuation.
• History of Grade ≥ 3 immune-related adverse event or any grade of immune-related neurologic or ocular adverse event while receiving immunotherapy.
  • Note: Patients who had endrocrine adverse events ≤ Grade 2 are allowed to enroll if they are stable on appropriate replacement therapy and asymptomatic.
• Other active malignancy < 6 months prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer, papillary thyroid cancer, prostate cancer, or carcinoma-in-situ of the cervix, or others curatively treated and now considered to be at less than 30% risk of relapse.

• Must have diagnosis of SOD1-ALS, and must have completed the End of Study Visit for either Parts A, B, or C of Study 233AS101 (NCT02623699) (i.e., were not withdrawn).
• If taking riluzole, must be receiving a stable dose for ≥ 30 days prior to Day 1. 
• For participants of childbearing potential must agree to practice effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment. 
• Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator. 
• Participants from Study 233AS101 Parts A and B must have a washout ≥ 16 weeks between the last dose of study treatment received in Study 233AS101 and the first dose of BIIB067 received in the current Study 233AS102.
• If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1.
  • Edaravone may not be administered on dosing days during this study.

• History of allergies to a broad range of anesthetics. 
• Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally and could place a participant at an increased risk for bleeding during or after a Lumbar Puncture (LP) procedure. These risks could include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other abnormalities) and underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand's disease, liver disease).
• Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter. 
• Prior or current treatment with small interfering ribonucleic acid (RNA), stem cell therapy, or gene therapy. 
• Treatment with another investigational drug, biological agent (excluding BIIB067), or device within 1 month or 5 half-lives of study agent, whichever is longer.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period. 
• Female participants who are pregnant or currently breastfeeding. 
• Current enrollment in any other interventional study. 
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine. 
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study. 
• Presence of an implanted intravenous port/catheter.
  • NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

• Subject must be ≥ 18 years and ≤ 75 years of age.
• Body weight of ≥ 40 kg (88.2 lb) at the time of signing the informed consent form (ICF)/assent form.
  • Note: Countries or sites with local restrictions that prohibit enrollment of adolescents (aged 12 to 17 years inclusive) will only enroll subjects who are 18 years of age or older. Enrollment of adolescent subjects will begin only after the applicable regulatory requirements for enrolling subjects in that age group have been satisfied and the necessary health authority approvals have been granted. Where national or regional guidelines for the definition of adolescence differ from the definition stated above, the national or regional guidelines may be used to determine eligibility.
• Subject has histologic evidence of EoE, defined as a peak count of ≥ 15 eosinophils per high-power field (hpf) at any 2 levels of the esophagus (proximal, mid, and/or distal) when off anti-inflammatory therapy (eg, corticosteroids, see Exclusion Criterion 7) for EoE. The histologic criterion for diagnosis of EoE must be confirmed by a centrally read histological assessment of an EGD specimen during the Screening Period prior to randomization.
• Subject has symptoms of dysphagia of at least 4 DD, as assessed with the mDSD instrument, over the last 2 consecutive weeks (14 days) prior to Day 1 when off anti- inflammatory therapy (eg, corticosteroids, see Exclusion Criterion 7) for EoE. Subjects are required to have at least 11 days of diary data out of the final 14-day period of screening mDSD collection in order to be enrolled in the study. During these 11 days, responses to questions 2 through 5 of the mDSD instrument must be complete.
• Subject must have previously received an adequate trial of proton-pump inhibitor (PPI) medication (8 weeks per guidance, Dellon, 2013) that did not provide complete response to EoE, or the subject remains symptomatic with continued use (Dellon, 2018b; Lucendo, 2017). Prospective subjects who discontinued use of a PPI must not have received a PPI for at least 4 weeks before their first Screening Visit and must agree not to restart a PPI during the study.  If a prospective subject is receiving a PPI medication at screening, he or she must have been receiving a stable dose for at least 4 weeks prior to the first Screening Visit and agree to continue the same dose throughout the study.
• Subject must either:
  • be naïve or have had an adequate response to corticosteroid therapy (i.e., classified as Steroid Responders/Naïve); or
  • have had an inadequate response to corticosteroid therapy and is not considered to be a candidate for continued corticosteroid therapy, or is intolerant to corticosteroid therapy. For subjects who have previously received systemic or swallowed topical corticosteroids for EoE, designation of the status of Steroid Inadequate Responders/Intolerant will include either of the following definitions. Note that if any of the below criteria are met, a subject will be deemed Steroid Inadequate Responders/Intolerant (approximately 70% of the study population) and cannot be classified as Steroid Responders/Naïve (approximately 30% of the study population).
    • Inadequate response to corticosteroid therapy (failed to respond or lost response) and not considered a candidate for continued corticosteroid therapy: subjects who have had a trial of at least 6 weeks of swallowed topical corticosteroid treatment; or
    • 4 weeks of systemic corticosteroids at doses in accordance to published guidelines for the management of EoE (Lucendo, 2017), or a trial for the treatment duration specified in the prescribing information for approved products and judged by the treating physician as not achieving clinical improvement or having clinical improvement initially but lost response while on therapy;
• • Intolerant to corticosteroid therapy: subjects who initiated systemic or swallowed topical corticosteroid treatment but were unable to achieve treatment durations or dose levels due to intolerance because of side effects, including intolerance from use of corticosteroids for conditions other than EoE, or subjects with underlying conditions in which corticosteroid use is not recommended or contraindicated.
• Documentation of type of therapy, treatment duration, and outcome details will be collected when possible.
• Subjects must agree to maintain a stable diet (including any food elimination diet for the treatment of food allergy or EoE) from the first Screening Visit and throughout the duration of the study, and subjects must have maintained a stable diet for at least 4 weeks prior to the first Screening Visit. Subjects must agree not to introduce any changes in their diet while participating in the study.
• Subjects currently receiving inhaled corticosteroids, leukotriene receptor antagonists (e.g., montelukast), or mast cell stabilizers (e.g., cromolyn sodium) for indications other than EoE, or medium potency topical corticosteroids (eg, mometasone furoate cream or lotion) for dermatologic conditions, must maintain stable doses/regimens for at least 4 weeks prior to the first Screening Visit and regimens must remain stable throughout the duration of the study. If recently discontinued, the medication must have been discontinued at least 4 weeks prior to the first Screening Visit.
• Female subjects of childbearing potential must agree to practice a highly effective method of contraception. Highly effective methods of contraception are those that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly.
• A female of childbearing potential (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 (ie, has had menses at any time in the preceding 24 consecutive months) and must:
• • Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study and through the Final 16-week Safety Follow-up Visit. 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, highly effective contraception without interruption throughout the study and for 5 months after the last dose of IP. Acceptable methods of birth control in this study are the following (birth control must be effective by the time the FCBP subject is randomized into the study [e.g., hormonal contraception should be initiated at least 28 days before randomization]):
    • combined hormonal (estrogen and progestogen containing) contraception, which may be oral, intravaginal, or transdermal;
    • progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable placement of an intrauterine device (IUD);
    • placement of an intrauterine hormone-releasing system (IUS);
    • bilateral tubal ligation; or bilateral tubal occlusion (if an implantable device was recently placed, the subject must use an additional effective method of birth control until full occlusion has been confirmed and documented);
    • vasectomized partner (vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the FCBP and has received medical assessment of the surgical success);
    • sexual abstinence.
• Subject is willing to receive weekly SC injections throughout the study.
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. For subjects less than 18 years of age, subject assent must be obtained, and parental/legal representative consent is required.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• True abstinence is acceptable when this is the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and lactational amenorrhea method are not acceptable methods of contraception.

• Subject has clinical or endoscopic evidence of the presence of any other disease that may interfere with or affect the histologic, endoscopic, and clinical symptom endpoints for this study (eg, erosive esophagitis Los Angeles [LA] classification Grade B or above, Barrett's esophagus, esophageal lichen planus, upper gastrointestinal bleed, achalasia, inflammatory bowel disease, diagnosed eosinophilic gastroenteritis [clinical symptoms and/or EGD findings and confirmatory eosinophilia in gastric and/or duodenal mucosa], or significant hiatal hernia [> 3 cm], etc.).
• Subject demonstrates presence of esophageal varices.
• Subject has a known active Helicobacter pylori infection and/or is currently being treated for this condition.
• Subject has evidence of a severe endoscopic structural abnormality in the esophagus (e.g., high-grade stenosis where an 8- to 10-mm endoscope could not pass through the stricture without dilation at the time of the screening EGD).
• Subject had esophageal dilation for symptom relief during the Screening Period or within 8 weeks prior to the first Screening Visit, or esophageal dilation is anticipated to be performed within 48 weeks of dosing during the study.
• Subject demonstrates evidence of immunosuppression or is receiving systemic immunosuppressive or immunomodulating drugs (e.g., anti-IL-13 antibodies [except IP in this study], IL-4 receptor alpha antagonist antibodies [eg, dupilumab], anti-IL-5 antibodies, anti-IL-17 antibodies, anti-immunoglobulin E [IgE] antibodies, α4β7 integrin inhibitor antibodies, or any other monoclonal antibody, methotrexate, cyclosporine, azathioprine, mercaptopurine, interferon alpha [IFNα], tumor necrosis factor alpha [TNFα] inhibitors, etc.) within 5 drug half-lives prior to the first Screening Visit. Any use of these medications will be prohibited during the study.
• Subject is currently receiving systemic or swallowed topical corticosteroid medication. Prospective subjects with EoE previously treated with a corticosteroid must not have received a systemic corticosteroid within 8 weeks or swallowed topical corticosteroid within 4 weeks of the first Screening Visit.
• Subject is currently receiving a high potency topical corticosteroid (e.g., augmented betamethasone dipropionate, clobetasol propionate, etc.) for dermatologic use. Prospective subjects must not have received a high potency topical corticosteroid for dermatologic use within 8 weeks of the first Screening Visit. Any use will be prohibited during the study.
• Subject is currently receiving a leukotriene receptor antagonist (e.g., montelukast) or mast cell stabilizer (e.g., cromolyn sodium) for the indication of EoE. Subjects must not have received a leukotriene receptor antagonist or mast cell stabilizer for EoE within 4 weeks of the first Screening Visit. Any use for the treatment of EoE during the study will be prohibited.
• Subject is currently successfully treated for EoE with dietary modifications (e.g., food elimination diet) and is able to fully adhere to the diet resulting in a complete response to EoE (i.e., the subject does not meet the symptoms of dysphagia requirement of at least 4 DD and histologic criterion for diagnosis of EoE per Section 4.2, Inclusion Criteria 2 and 3).
• Subject has received oral or sublingual immunotherapy within 6 months of the first Screening Visit; any use will be prohibited during the study. Subjects receiving SC immunotherapy may participate but must be on stable doses for at least 3 months prior to the first Screening Visit and during the study.
• Subject is receiving concurrent treatment with another IP, including through participation in an interventional trial for COVID-19. Prospective subjects may not participate in a concurrent IP study or have received an IP within 5 drug half-lives prior to signing the ICF/assent for this study. Further, for subjects who received an investigational COVID-19 vaccine as part of a clinical trial prior to the first Screening Visit, enrollment must be delayed until the biologic impact of the vaccine is stabilized, as determined by discussion between the Investigator and the Clinical Trial Physician.
• Subject has received a live attenuated vaccine within one month prior to the first Screening Visit or anticipates the need to be vaccinated with a live attenuated vaccine during the course of the study. Administration of any live attenuated vaccine will be prohibited during the study through the Final 16-week Safety Follow-up Visit.
• Subject has previously received CC-93538 treatment (formerly known as RPC4046 and ABT-308) through participation in the Phase 2 Study, RPC02-201, or any Phase 1 clinical study.
• Subject has any other disease that would make conduct of the protocol or interpretation of the study results difficult or that would put the prospective subject at risk by participating in the study (eg, severe uncontrolled asthma, infection causing eosinophilia, hypereosinophilic syndrome, gastritis, colitis, celiac disease, Mendelian disorder associated with EoE, or cardiovascular condition, or neurologic or psychiatric illness that compromises the prospective subject's ability to accurately document symptoms of EoE).
• Subject has liver function impairment or persisting elevations of aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) that are 2 times the upper limit of normal (ULN), or total bilirubin 1.5 times the ULN. Subjects with elevations that are not clinically significant in total bilirubin associated with Gilbert’s syndrome may participate.
• Subject has an active parasitic/helminthic infection or a suspected parasitic/helminthic infection. Subjects with suspected infections may participate if clinical and laboratory assessments, if needed, rule out active infection prior to randomization.
• Subject has an ongoing infection (e.g., hepatitis B or C, human immunodeficiency virus [HIV], or tuberculosis as defined by standard medical guidelines).
• Subject had a previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 4 weeks prior to screening. Symptoms must have completely resolved and based on Investigator assessment in consultation with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
• Subject has known hereditary fructose intolerance (HFI).
• Subject is pregnant or lactating.
• Subject has a history of idiopathic anaphylaxis or a major immunologic reaction (such as anaphylactic reaction, anaphylactoid reaction, or serum sickness) to an immunoglobulin G (IgG) containing agent.
• Subject has a history of cancer or lymphoproliferative disease, other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or adequately treated cervical carcinoma in situ, within 5 years of screening.
• Subject has a history of alcohol or drug abuse within 5 years prior to initiation of screening.
• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.

• Females, 18 to 35 years of age (pregnancy assessed by self-report).
• Non-pregnant.

• Male.
• Known pregnancy (by self-report.
• Known genetic disorder (by self-report).
• Cancer history (including any form of skin cancer).
• Diabetes.
• Failure to meet 21 CFR 1271 donor eligibility criteria based on responses to a donor eligibility questionnaire.
• Positive infectious disease result on any test in the infectious disease screening panel (including HBsAg Screen, HBc Total Ab, HBV NAT, HCV NAT, HIV-1 NAT, HCV Ab Screen, HIV-1/-2, plus O Ab Screen, HTLV-I/-II Ab Screen, T. cruzi Total Ab, Syphilis Ab Screen, CMV Total Ab, West Nile Virus NAT).
• Medical records review.
• Physical exam.    

Eligibility last updated 1/12/23. Questions regarding updates should be directed to the study team contact. 

Key

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

Eligibility last updated 6/27/23. Questions regarding updates should be directed to the study team contact.

• Women ≥ 35 years old and ≤ 75 years old.
• Women that meet at least one of the following:
  • NCI-BCRAT 5-year risk (> 3%) or that shows at least moderate evidence of treatment benefit outweighing risk according to the US Preventative Services Task Force or IBIS (version 8) risk calculator (> 8% for the 10-year risk);
  • History of atypical hyperplasia (30% lifetime risk for developing breast cancer);
  • LCIS (approximately 20% lifetime risk for developing breast cancer);
  • Status post-surgery (lumpectomy or unilateral mastectomy) for ER positive DCIS;
  • Status post-surgery (lumpectomy or unilateral mastectomy) for pleomorphic LCIS.

Exclusion Criteria:

• Women whose BCRAT falls below the threshold moderate according to the US Preventative Task Force or IBIS (version 8) 10 year risk of < 8%; OR do not have a surgical finding that demonstrates increased risk of developing invasive breast cancer.
• Women with known BRCA1 and BRCA2 mutations.
• Women with known contraindications to tamoxifen, raloxifene, exemestane or anastrozole.
• Women unable to give informed consent.
• Prior history of invasive breast cancer.
• At-risk women due to prior radiation therapy to the chest.
• Prior use of preventive medications (tamoxifen, raloxifene, exemestane or anastrozole) for breast cancer prevention.

• A female of childbearing potential is a sexually mature female who:
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Stage II-III colorectal cancer patients scheduled to receive oxaliplatin 510 mg/m^2 (cumulative dose) over 12 weeks as a component of adjuvant leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX) treatment, in which patients are scheduled to receive oxaliplatin 85 mg/m^2 every 2 weeks for 12 weeks (i.e., 6 cycles), or adjuvant capecitabine and oxaliplatin (CAPOX) treatment, in which patients are scheduled to receive oxaliplatin 135 mg/m^2 every 3 weeks for 12 weeks (i.e., 4 cycles).
• No prior neurotoxic chemotherapy.
• No pre-existing clinical or pre-clinical peripheral neuropathy from any cause.
• No history of seizure disorder.
• No history of narrow-angle glaucoma.
• No symptoms of or history of schizophrenia, bipolar disease, suicidal thoughts and/or a major depression.
• No serious eating disorder such as bulimia or anorexia.
• No known diagnosis of ethanol (ETOH) addiction/dependence within the past 10 years.
• Concomitant medications:
  • No concomitant use of other adjuvant pharmacologic interventions (e.g., gabapentin, pregabalin, venlafaxine) with known or hypothesized efficacy for peripheral neuropathy. Must be discontinued at least 7 days prior to start of protocol treatment;
  • No anticipated or concurrent use of any antidepressant or serotonin-altering agent known to interact with duloxetine, due to concern regarding cumulative toxicity and potential drug interactions.
  • Use of a monoamine oxidase inhibitor (MAOI) or other antidepressants must be discontinued at least 14 days prior to start of protocol treatment;
  • No concomitant treatment with strong CYP1A2 and CYP2D6 inhibitors;
  • Chronic concomitant treatment with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants, phenothiazines, and Type 1C antiarrhythmics should be approached with caution. Concomitant administration of duloxetine and thioridazine should be avoided;
  • No use of warfarin or heparin products.
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential, a negative pregnancy test done ≤ 7 days prior to registration is required.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• In order to complete the mandatory patient-completed measure.
• Patients must be able to speak and read English.
• Calculated creatinine clearance > 30 mL/min.
• Aspartate aminotransferases (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤ 3 x upper limit of normal (ULN).