PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have been diagnosed with CLL and have > 5000 B-cells per uL of peripheral blood at any point during the course of their disease.
• This blood submission is mandatory prior to registration/randomization to perform FISH centrally that will be used for stratification. It should be obtained as soon after preregistration as possible.

REGISTRATION ELIGIBILITY CRITERIA (STEP 1) 

• Patients must be diagnosed with CLL in accordance with 2018 IWCLL criteria [28] that includes all of the following:
  • ≥ 5 x10^9 B lymphocytes (5000/μL) in the peripheral blood measured by flow cytometry at any point in the course of the disease;
  • On local morphologic review, the leukemic cells must be small mature lymphocytes, and prolymphocytes must not exceed 55% of the blood lymphocytes;
  • CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell population, which express the B cell surface markers of CD19 and CD20, as well as the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or lack of CD23 expression in >10% of cells must lack t(11;14) translocation by interphase cytogenetics.
• Patients must be intermediate or high-risk Rai stage CLL.
  • Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus any of the following: enlarged lymph nodes, hepatomegaly, or splenomegaly'
  • High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to autoimmune hemolytic anemia or thrombocytopenia.
• Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which includes at least one of the following criteria:
  • Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or thrombocytopenia);
  • Massive (≥ 6 cm below the costal margin), progressive or symptomatic splenomegaly;
  • Massive nodes (≥ 10 cm) or progressive or symptomatic lymphadenopathy;
  • Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2 month period;
  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy;
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine);
  • Constitutional symptoms, which include any of the following:
    • Unintentional weight loss of 10% or more within 6 months;
    • Significant fatigue;
    • Fevers >100.5 degrees F for 2 weeks or more without evidence of infection;
    • Night sweats ≥1 month without evidence of infection.
• Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids).
• Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration.
• Age ≥ 65 years.
• ECOG performance status 0-2.
• Required initial laboratory values.
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3 except if due to bone marrow involvement.
• Platelet Count (untransfused) ≥ 30,000/mm^3.
• Calc. Creatinine Clearance ≥ 40 mL/min (by Cockcroft-Gault).
• Bilirubin ≤ 1.5 x upper limit of normal (ULN) except if due to liver involvement, hemolysis, or Gilbert’s disease.
• AST / ALT ≤ 2.5 x upper limit of normal (ULN) except if due to liver involvement.
• Patients must not have any history of Richter’s transformation or prolymphocytic leukemia (prolymphocytes in blood > 55%).
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
  • Please note: IVIG can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, must have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load.
• Patients with Class III or Class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligible.
• Patients who have had a myocardial infarction, intracranial bleed, or stroke within the past 6 months are not eligible.
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Patients must not be receiving active systemic anticoagulation with heparin or warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to registration on the study.
• Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days prior to registration on the study. 
• Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed.
• Patients must discontinue the drug 14 days prior to registration on the study.
• Patients must not require more than 20 mg prednisone or equivalent corticosteroid daily.
• Patients must not have uncontrolled active systemic infection requiring intravenous antibiotics.
• Central FISH blood results are mandatory prior to registration/randomization for it will be used for stratification.
• Patients must be able to swallow capsules and not have the following conditions:  disease significantly affecting gastrointestinal absorption, resection of the stomach or small bowel, partial or complete bowel obstruction.
• Patients must not have a known allergy to mannitol.
• Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions).
• Patients may not have had major surgery within 10 days prior to registration, or minor surgery within 7 days prior to registration. Examples of minor surgery include dental surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint. The decision about whether a surgery is major or minor can be made at the discretion of the treating physician.
• Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase for prophylaxis/treatment of TLS.

RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

• Completion of treatment through Cycle 14 Day 28, and remain on ibrutinib therapy.
• Receipt of central BM MRD results.
• Response assessment completed per Section 5.0 with CR determination.

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

Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing
potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,
ovarian suppression or any other reversible reason.

- No use of immunosuppressive medication within 7 days prior to randomization except:

- Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intra-articular injection);

- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent;

- Steroids as premedication for hypersensitivity reactions (e.g., computed
tomography [CT] scan premedication).

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.

- Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease
not requiring immunosuppressive treatment are eligible.

- Absolute neutrophil count (ANC) ≥ 1,000/mm^3.

- Platelet count ≥ 100,000/mm^3.

- Hemoglobin ≥ 8 g/dL.

- Calculated (Calc.) creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault
equation: (140
•age) × weight (kg)/(serum creatinine [mg/dL] × 72).

- Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN).

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (or ≤ 5
x ULN for patients with liver metastases or Gilbert's disease).

- Urine protein creatinine (UPC) ratio ≤ 1 or 24-hour protein < 1 g.

Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3
minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard;

- Any history of congenital long QT syndrome;

- Stroke, transient ischemic attack (TIA), myocardial infarction, or other
symptomatic ischemic event or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism (DVT/PE) within 6 months before
randomization. Subjects with a diagnosis of incidental, subsegmental PE or
DVT within 6 months are allowed if asymptomatic and stable at screening and
treated with low molecular weight heparin (LMWH) or the direct factor Xa
inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before
randomization. Non-symptomatic white matter disease in the brain is
acceptable;

- No significant gastrointestinal disorders, particularly those associated with a
high risk of perforation or fistula formation including unresolved active peptic
ulcer disease, cholecystitis, diverticulitis, symptomatic cholangitis or
appendicitis, or malabsorption syndrome within 28 days of randomization.

- No other clinically significant disorders such as:

- Any active infection requiring systemic treatment within 14 days before
randomization. Subjects receiving oral (including prophylactic) antibiotics
with no symptoms of infection at randomization are eligible;

- Serious non-healing wound/ulcer/bone fracture within 28 days before
randomization;

- History of organ or allogeneic stem cell transplant;

- No persisting toxicity related to prior therapy grade > 2 constituting a safety
risk based on the investigator's judgment;

- No diagnosis of any other malignancy within 3 years prior to randomization,
except for locally curable cancers that have been adequately treated such as
basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of
the cervix, Gleason < 7 prostate cancer on surveillance without any plans for
treatment intervention (e.g., surgery, radiation, or castration), or prostate
cancer that has been adequately treated with prostatectomy or radiotherapy and
currently with no evidence of disease or symptoms and no indication for treatment;

- No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct
thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or
platelet inhibitors (e.g., clopidogrel).

- Allowed anticoagulants are the following:

- Prophylactic use of low-dose aspirin for cardio-protection (per local
applicable guidelines) and low-dose low molecular weight heparins
(LMWH).Therapeutic doses of LMWH or anticoagulation with direct factor
Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without
known brain metastases who are on a stable dose of the anticoagulant
for at least 1 week before first dose of study treatment without clinically
significant hemorrhagic complications from the anticoagulation regimen or the tumor.

- Physicians should consider whether any of the following may render the patient
inappropriate for this protocol:

- Psychiatric illness which would prevent the patient from giving informed consent;

- Uncontrolled medical conditions which, in the opinion of the treating physician,
would make this protocol unreasonably hazardous for the patient;

- Patients who cannot swallow oral formulations of the agent(s).

In addition:

- Women and men of reproductive potential should agree to use an appropriate method of
birth control throughout their participation in this study due to the teratogenic
potential of the therapy utilized in this trial. Include as applicable: Appropriate
methods of birth control include abstinence, oral contraceptives, implantable hormonal
contraceptives or double barrier method (diaphragm plus condom);

- Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's
syndrome and psoriasis controlled with topical medication and or steroids equivalent
to < 10 mg prednisone daily, not on immunosuppressive medications and patients with
positive serology are eligible. Patients with vitiligo, endocrine deficiencies including
hypo or hyper thyroid disease managed with replacement, diabetes type 1 are
eligible.

- Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (e.g., male or female condom) during the study and continue
for 4 months after the last dose of study drugs, even if oral contraceptives are also
used.

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

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

• ≥ 18 years of age.
• Biopsy proven Focal Segmental Glomerulosclerosis (FSGS) lesion
• Foot process effacement ≥ 80% on electron microscopy.
• Presence of nephrotic syndrome (proteinuria > 3.5g/24hrs and serum albumin < 3.5 g/dl) prior to initiation of immunosuppressive therapy.
• Resistant or dependent on therapy, including corticosteroids or calcineurin inhibitors or who have failed rituximab. Patient who have contraindication to or refuse to take high dose corticosteroids are allowed. 

• Genetic or secondary forms of FSGS.
• Hepatitis B, C or HIV positive.
• Pregnant or breast-feeding.
• Active infection.
• Kidney transplant.
• Anemia with Hgb < 8.0 g/dL.
• Thrombocytopenia with platelet count < 100’000.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication.
• Patients who have received cyclophosphamide in the last 6 months.
• Patients who received rituximab previously with CD20 count of < 5 cells/microliter  at the time of enrollment.
• For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of less than (<) 1 percent (%) per year, during the treatment period and for at least 18 months after the last dose of study drug.
• For men: agreement to remain abstinent or use two adequate methods for contraception, including at least one method with failure rate of less than 1% per year during the treatment period and for at least 6 months (180 days) after the last dose of drug.

• Failure to respond to at least two trials of anti-seizure drugs with different mechanisms of action;
• Normal MRI.

• Active immunomodulatory therapy;
• Autoimmune disorder;
• Signs or symptoms consistent with comorbid infection;
• ncological comorbidity.

• Adult males and females between 18 and 60 years of age, inclusive at the time of signing the informed consent document.
• Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
• Diagnosis of cyclic vomiting syndrome (CVS) using the Rome IV diagnostic criteria and must have:
  • Stereotypical episodes of acute onset vomiting lasting < 1 week;
  • At least 3 discrete episodes of vomiting in the prior year and 2 episodes in the past 6 months, occurring at least 1 week apart;
  • Absence of vomiting between episodes (but milder symptoms may be present);
  • Symptoms must be present for the past 3 months with onset at least 6 months prior.
• Has a prodrome or pre-emetic symptoms for approximately half of their “typical” CVS episodes.
• If of reproductive age, female participants and female partners of male participants, willing and able to use a medically highly effective form of birth control from at least 4 weeks prior to Baseline until at least 30 days following last dose of study drug. Examples of medically highly effective forms of birth control are:
  • Surgical sterility (hysterectomy or bilateral ligation) or post‑menopausal (cessation of menses for at least 12 months prior to screening);
  • Sexual partner is sterile, or of the same sex;
  • Implants of levonorgestrel in females;
  • Oral contraceptive (combined, patch, vaginal ring, injectable, implant) in females;
  • Double-barrier method (any combination of physical and chemical methods);
  • Intrauterine device with a failure rate less than 1% per year.
• Male participants must:
  • Agree to use, with their partners, one of the highly effective contraceptive methods listed in Inclusion Criterion 5, from Baseline until at least 30 days following last dose of study drug;
  • Refrain from donating sperm during the study and for at least 30 days after the end of the study.
• Otherwise healthy, as determined by the responsible physician, based on a medical evaluation including history, physical examination, vital signs, electrocardiograms (ECGs) and laboratory tests assessed at the screening visit.
• Negative urine tests for selected drugs of abuse and alcohol breath test at Screening.
• Note: Patients with a positive urine drug screen for benzodiazepines or opiates may be allowed in the study provided the drug was prescribed by a physician.
• Willing and able to adhere to overall study visit schedule, procedures and other protocol requirements.

• Any significant medical or psychiatric condition that could, in the Investigator’s opinion, compromise the subject’s safety or interfere with the completion of this protocol.
• Any condition, including the presence of laboratory abnormalities or pulmonary condition, which according to the Investigator places the subject at unacceptable risk if he/she were to participate in the study.
• A diagnosis of any gastrointestinal disorder other than CVS that in the judgement of the Investigator could compromise the subject’s safety or interfere with the interpretation of safety or efficacy data.
• History of clinically significant neurologic (e.g., seizures), cardiac, pulmonary (e.g., asthma, COPD), metabolic, renal, or hepatic conditions.
• Use drugs known to prolong QTc. ECG findings of PR interval > 220 msec or QRS duration > 120 msec or QTcF interval > 450 msec for men and 470 msec for women obtained at screening visit or prior to the first dose of study drug.
• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), serum creatinine, or total bilirubin > 1.5 upper limit of normal (ULN) at screening or prior to the first dose of study drug. These laboratory tests may be repeated once, if they are abnormal on first screening, and if there is a medical reason to believe the results may be inaccurate. If the repeat test is within the reference range, the subject may be included only if the Investigator considers that the previous finding will not compromise the subject’s safety and will not interfere with the interpretation of safety data.
• Positive blood screen for human immunodeficiency virus (HIV antibody), hepatitis B virus surface antigen, or hepatitis C virus antibody at screening.
• History of alcohol or illicit drug abuse within 1 year before the first dose of study drug.
• Daily use of marijuana.
  • Note: Occasional use of THC/cannabinoid products is allowed in the study.
• Participation in a clinical trial and receipt of an investigational medication or a new chemical entity within 90 days, 5 half-lives, if known, or twice the duration of the biological effect of any medication (whichever is longer) prior to the first dose of current study drug.
• Donation of blood, plasma or other blood products or blood collection in excess of 470 mL within 8 weeks prior to dosing.
• Known history of sensitivity to any of the study drugs or components thereof, or to other 5-HT3 receptor antagonists, or a history of medication allergy or other allergy that, in the opinion of the Investigator, contraindicates study participation.
• Major surgery within 4 weeks of screening that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the Investigator.
• Uncontrolled current illness (i.e., active infection).
• Has a current or a history of cancer, with the exception of basal cell carcinoma.

Eligibility last updated 2/24/22. Questions regarding updates should be directed to the study team contact.

• Disabling (moderate-to-severe) PTS, defined by a) presence of chronic venous disease > 3 months duration in a leg with history of DVT, as determined by the site principal investigator or a physician co-investigator; and b) substantial limitation of daily activities or work capacity due to venous symptoms or an open venous ulcer, per the same investigator.
• Ipsilateral iliac vein obstruction documented within 3 months prior to screening by either:
  • Occlusion or >50% stenosis of the iliac vein on venogram, CT venogram, MR venogram, or intravascular ultrasound (IVUS); or
  • Air plethysmography showing deep venous obstruction of the ipsilateral leg (reduced venous outflow fraction), and ultrasound showing echogenic material in the ipsilateral iliac vein and non-phasic continuous Doppler flow in the ipsilateral common femoral vein (CFV) in the presence of normal phasic Doppler flow in the contralateral CFV.

• Age less than 18 years.
• Acute ipsilateral proximal DVT episode within the last 3 months, or acute contralateral DVT for which thrombolytic therapy is planned.
• Lack of suitable inflow into the ipsilateral common femoral vein per the treating physician.
• Previous stent placement in the infrarenal IVC or ipsilateral iliac or common femoral vein.
• Absence of PTS of at least moderate severity.
• Chronic arterial limb ischemia (ankle-brachial index < 0.5 within the previous 1 month) in the ipsilateral leg (if peripheral arterial disease is present or suspected, an ankle-brachial index should be obtained and documented).
• Presence of open venous ulcer > 50 cm2 area, suspicion for active ulcer infection, or visualization of bone or tendon within the ulcer in the ipsilateral leg.
• Inability to tolerate endovascular procedure due to acute illness, or general health.
• Severe allergy to iodinated contrast refractory to steroid premedication.
• Known allergy to stent or catheter components.
• Hemoglobin < 8.0 g/dl, uncorrectable INR > 3.05, or platelet count < 75,000/ml.
• Severe renal impairment (on chronic dialysis or estimated GFR < 30 ml/min).
• Disseminated intravascular coagulation or other major bleeding diathesis.
• Pregnancy (positive pregnancy test).
• Life-expectancy < 6 months or chronically non-ambulatory for reasons other than PTS.
• Inability to provide informed consent or to comply with study assessments.
  • Note:  patients who initially meet an exclusion criterion can have eligibility re-evaluated on a subsequent occasion.

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

Eligibility last updated 12/15/22. Questions regarding updates should be directed to the study team contact.

• Male and female adults diagnosed with celiac disease (positive celiac serology plus confirmed biopsy) for at least 6 months.
• On a gluten-free diet for at least 6 months.
• Experiencing symptoms (i.e., abdominal pain, abdominal cramping, bloating, gas, diarrhea, loose stool, or nausea).
• Willing to maintain current gluten-free diet throughout participation in the study. 

• Refractory celiac disease or severe complications of celiac disease.
• Chronic active GI disease other than celiac disease.

• Participant must be at least 12 years of age at the time of signing the ICF or informed assent form.
• Clinician confirmed diagnosis of EG/EGE for at least 3 months prior to screening.
• Participants who have documented previous diagnosis of eosinophilic gastritis, with or without duodenitis, or eosinophilic duodenitis alone. This will be confirmed by biopsy for the purpose of this study, defined as a gastric count of ≥ 30 eosinophils/hpf in at least 5 hpfs and and/or duodenal eosinophil count ≥30 eosinophils/hpf in at least 3 hpfs without any other cause for the gastrointestinal eosinophilia (e.g., parasitic or other infection or malignancy). Participants can have duodenal only disease and be enrolled in the duodenal only subject population. 
• At Visit 1 (screening), participants who in the investigator’s judgement have a history of symptoms of abdominal pain, nausea, bloating, early satiety, and/or loss of appetite to an extent that they would meet criteria 5 at Visit 2.
• At Visit 2 (randomisation), participants who are symptomatic, defined as having a mean SAGED score > 12 (on a 0 to 50 point scale) over the last 14 days of the run-in period.
• Must be adherent to daily PRO assessments:
  • Must complete 70% SAGED, DSQ, and Bristol Stool Form Scale assessments between Visit 1 and Visit 2; AND
  • Must have completed at least 8 of 14 SAGED assessments in the 14 days prior to randomization.
• If on background medications for EG/EGE during the study, background medications have been stable for at least 4 weeks prior to the run-in period.
  • Patient must agree not to change type of background medication or dosage during the study unless medically indicated or allowed by protocol during Part C OLE after Week 52 as clinically indicated. If a medication for EG/EGE (including swallowed steroids, systemic steroids and PPI) is discontinued prior to screening, there should be a washout period of at least 8 weeks prior to screening. 
• Negative serum pregnancy test for women of childbearing potential (WOCBP) at Visit 1 (enrollment).
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Female participants:
  • 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 amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age-specific requirements apply:
  • Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and have follicle stimulating hormone levels in the postmenopausal range.  Until FSH is documented to be within menopausal range, she should be treated as a WOCBP:
    • Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
• Female participants that are WOCBP must use one highly effective form of birth control. 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. WOCBP who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control, as defined below, from enrollment throughout the study and until at least 12 weeks after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together. All women of child bearing potential must have a negative serum pregnancy test result at Visit 1.
• Highly effective birth control methods include:
  • Combined (estrogen and progestogen ) hormonal contraception associated with ;inhibition of ovulation- oral, intravaginal, or transdermal
  • Progestogen-only hormonal contraception associated with inhibition of ovulation- oral, injectable, or implantable;
  • Intrauterine device;
  • Intrauterine hormone-releasing system;
  • Bilateral tubal occlusion;
  • Sexual abstinence, ie 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.
• Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

• Any disorder, including, but not limited to, cardiovascular, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could:
  • Affect the safety of the patient throughout the study;
  • Influence the findings of the studies or their interpretations;
  • Impede the patient’s ability to complete the entire duration of study.
• Other gastrointestinal disorders such as active Helicobacter pylori infection, history of achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel disease, or celiac disease.
• Hypereosinophilic syndrome or eosinophilic granulomatosis with polyangiitis.
• Current malignancy, or history of malignancy, except for patients who have had basal cell, 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 of 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, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis;
  • Alanine aminotransferase or aspartate aminotransferase level > 3 times the upper limit of normal, confirmed by repeated testing during the run-in period. Transient increase of aspartate aminotransferase/alanine aminotransferase 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.
• Any clinically 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.
• Known immunodeficiency disorder including testing positive for HIV.
• Concomitant use of immunosuppressive medication (including but not limited to:
  • methotrexate, cyclosporine, and azathioprine.
• Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent or assent is obtained.
• Receipt of live attenuated vaccines 30 days prior to date of informed consent or assent.
• Receipt of inactive vaccines within 7 days of informed consent or assent.
• 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.
• Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives prior to randomization, whichever is longer.
• Participants with a known hypersensitivity to benralizumab or any of the excipients of the product.
• Initiation or change of a food-elimination diet regimen or re-introduction of a previously eliminated food group from 6 weeks prior to start of the run-in period and unable or unwilling to remain on a stable diet until the completion of Week 52.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Judgment by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements.
• For women: currently pregnant confirmed with positive pregnancy test or breast-feeding.

Eligibility last updated 1/18/22. Questions regarding updates should be directed to the study team contact.

• Men or women of any ethnic group aged 22 and older.
• Primary skin lesion suggestive of melanoma, basal cell carcinoma, and/or squamous cell carcinoma that requires biopsy to assess risk of malignancy.
• Patient is willing and able to read, understand and sign the ICF.

• Lesion < 2.5mm in diameter or > 15mm in diameter.Lesion surface not accessible (e.g., inside ears, under nails, completely covered by a crust or scale)
• Lesion on area of crust, psoriasis, eczema or similar skin condition.
• Lesion has erosion and/or ulceration with no area > 2.5mm intact.
• Lesion has foreign matter (e.g., tattoo, splinter, dermoscopy oils, or other medicated or non-medicated topical solutions).
• Lesion in which the device tip cannot be placed entirely within the border of the targeted area.
• Lesion located on acral skin (e.g., sole or palms).
• Lesion located within 1 cm of the eye.
• Lesion on or adjacent to scars, areas previously biopsied, or areas subjected to any past surgical intervention.
• Lesion located on mucosal surfaces (e.g., genitals, lips).
• Lesion located on acute sunburn.
• Six (6) or more lesions suggestive of melanoma, basal cell carcinoma, and/or squamous cell carcinoma requiring biopsy to assess risk of malignancy.
• Dementia or other neurologic, physical or psychological limitation that would prevent the patient from signing informed consent.

• Adult patients (age 18 and over).
• Active cancer diagnosis.
• Admitted to the inpatient setting.
• Grade 3-4 oral mucositis per the World Health Organization (WHO).
• Grade 3: soreness and erythema, able to eat solid food.
• Grade 4: soreness and erythema, able to tolerate liquid diet only.
• Patient reports oropharyngeal pain.
• Able to provide informed consent.

• Pediatric age (under 18 years old).
• Any contraindication to methylene blue.
• Pregnant women.

Eligibility last updated 10/25/22. Questions regarding updates should be directed to the study team contact.

1. Male or female patients, age ≥18 years
2. Patients with a histological/cytological or radiological diagnosis of HCC (mixed HCC cholangiocarcinoma may be included; patients who are candidates for surgical and non-surgical treatment, as well as those being followed without specific HCC therapy may be included)

1. Inability to provide written informed consent

- Note: Women of childbearing potential (WOCBP) and Women not of childbearing potential are eligible to participate. Women of childbearing potential should use an approved method of birth control and agrees to continue to use this method for the duration of the study (and for 30 days after taking the last dose of investigational product). o Acceptable methods of contraception include abstinence, female subject/partner's use of hormonal contraceptive (oral, implanted, or injected) in conjunction with a barrier method (WOCBP only), female subject/partner's use of an intrauterine device (IUD), or if the female subject/partner is surgically sterile or 2 years post-menopausal. All male subjects/partners of WOCBP must agree to consistently and correctly use a condom for the duration of the study and for 30 days after taking the study drug. In addition, subjects may not donate ova or donate sperm for the duration of the study and for 30 days after taking the last dose investigational product.

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

Eligibility last updated 12/29/23. 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.

Inclusion Criteria - Neurodegenerative Disease and Disorders :

• Age and gender matched to healthy participants with no known neurodegenerative disorder.
• Absence of primary psychoses including schizophrenia, bi-polar disorder or other (patients with co-morbid depression can be included)
• Ability to give, with or without caretaker, verbal or written consent.
• Currently diagnosed with AD, PDD, DLB, or MCI [(McKhann et al., 2011) (Emre et al., 2007), (McKeith et al., 2017), (Albert et al., 2011)] .

Exclusion Criteria
•Neurodegenerative Disease and Disorders:

• Recent (past 5 years) head injury, or older head injury with current symptoms.
• Regular (daily) use of opiate pain medications.
• Any eating disorders (anorexia, bulimia).
• History of marijuana/cannabis use (amount/ times per week).
• Excessive tobacco use (i.e. more than 10 cigarettes a day).
• Excessive alcohol (> 5 drinks daily) or caffeine (>10 cups daily).
• Any known clinically significant pulmonary (lung) disorders.
• Untreated/untreatable vision or hearing problems.
• Pregnant or nursing.
• Inadequate familiarity with the English language.
• Older than 90 years of age or younger than 40 years of age.

Inclusion Criteria
•Healthy Controls:

• Age and gender matched to patients diagnosed with neurodegenerative disorder.
• Absence of a neurological or psychiatric illness.
• Ability to give verbal and written consent.

Exclusion Criteria
•Healthy Controls:

• Any known sleep disorder (e.g., narcolepsy, severe sleep apnea, chronic insomnia).
• Recent (past 5 years) head injury, or older head injury with current symptoms.
• Regular use of opiate pain medications.
• Any eating disorders (anorexia, bulimia).
• Current use or a history of use of stimulants (e.g., amphetamine) or substance abuse.
• History of marijuana/cannabis use (amount/ times per week).
• Excessive tobacco use (i.e. more than 10 cigarettes a day).
• Any known neurological or psychiatric illnesses.
• Excessive alcohol (> 5 drinks daily) or caffeine (> 7 cups daily).
• Any known clinically significant pulmonary (lung) disorders.
• Untreated/untreatable vision or hearing problems.
• Pregnant or nursing.
• Inadequate familiarity with the English language.
• Older than 90 years of age or younger than 40 years of age.

Exclusion Criteria
•All Participants:

• Heart failure (i.e., myocardial infarction).
• Epilepsy (current episodes and medication in the past year).
• Known AIDs (HIV+) diagnosis
• Bipolar disorder.
• Severe/psychotic depression requiring immediate psychiatric hold because of danger to self or others. 

PSG SubStudy Only:

Inclusion Criteria
•REM sleep behavior disorder:

• Fulfill criteria for RBD based on polysomnography according to the standard International Classification of Sleep Disorders diagnostic criteria, 3rd edition (American Academy of Sleep Medicine 2014).
• Age and gender matched to healthy participants with no known neurodegenerative disorder.

Exclusion Criteria - (REM sleep behavior disorder):

• Recent (past 5 years) head injury or older head injury with current symptoms.
• Inadequate familiarity with the English languageepilepsy (current episodes and medication in the past year).
• Known AIDs (HIV+) diagnosis.
• Severe/psychotic depression requiring immediate psychiatric hold because of danger to self or others.

Inclusion Criteria
•Healthy Controls:

• Age and gender matched to patients diagnosed with REM sleep behavior disorder.
• Absence of a neurological illness.
• Ability to give verbal and written consent.

Exclusion Criteria
•Healthy Controls:

• Any known neurological illnesses.
• Iadequate familiarity with the English language.
• Known AIDs (HIV+) diagnosis.
• Severe/psychotic depression requiring immediate psychiatric hold because of danger to self or others. 

• Patients will not be excluded for controlled hypertension, diabetes, high cholesterol, mild to moderate sleep apnea or depression.
• Medical marijuana use will not be a cause for excluding a participant; however, current use will be documented.

Key

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

Eligibility last updated 4/18/23. Questions regarding updates should be directed to the study team contact.

• Patients must have 5 or more brain metastases as counted on a T1 contrast enhanced MRI obtained ≤ 30 days from randomization (maximum 15 brain metastases).
• Patients must have a pathological diagnosis (cytological or histological) of a non-hematopoietic malignancy.
• The largest brain metastasis must measure < 2.5 cm in maximal diameter. The total tumour volume must be 30 cm3 or less. Lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrast-enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g., xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumour volume.
• Centre must either have the ability to treat patients with either a Gamma Knife, Cyberknife, or a linear accelerator-based radiosurgery system, or access to a centre at which the trial is open which can treat with using one of these systems.
• Patient must be ≥ 18 years of age.
• Patient is able (i.e., sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French either alone or with assistance. The baseline assessment must be completed within required timelines, prior to randomization.
• Patient must also be able and willing to complete the neurocognitive testing without assistance from family and companions. Because this is one of the primary goals of this study, patients must be fluent in English or French, and fully testable in one of those languages.
• A patient that is able but unwilling to complete the questionnaires will be considered ineligible.
• ECOG performance status 0, 1, or 2.
• Creatinine clearance must be ≥ 30 ml/min within 28 days prior to registration.
• The Neurocognitive Testing examiner must have credentialing confirming completion of the neurocognitive testing training.
• The enrolling facility is credentialed by IROC to perform SRS and HA-WBRT
  •or have access to a centre where these treatments are credentialed and the study is open. The treating centre must have completed stereotactic radiosurgery credentialing of the specific system(s) to be used in study patients. The treating centre must have completed IMRT credentialing of the specific IMRT system(s) to be used in study patients for the purposes of HA-WBRT.
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures.
• Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• In accordance with CCTG policy, protocol treatment is to begin within 14 days of patient enrolment.
• Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. A woman is considered to be of "childbearing 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, or vasectomy/vasectomized partner. 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.
• Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of hCG, as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy.

• Pregnant or nursing women.
• Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Inability to complete a brain MRI.
• Known allergy to gadolinium.
• Prior cranial radiation therapy.
• Planned cytotoxic chemotherapy within 48 hours prior or after the SRS or HA-WBRT.
• Primary germ cell tumour, small cell carcinoma, or lymphoma.
• Widespread definitive leptomeningeal metastasis. This includes cranial nerve palsy, leptomeningeal carcinomatosis, ependymal involvement, cranial nerve involvement on imaging, suspicious linear meningeal enhancement, or cerebrospinal fluid (CSF) positive for tumour cells.
• A brain metastasis that is located ≤ 5 mm of the optic chiasm or either optic nerve.
• Surgical resection of a brain metastasis (stereotactic biopsies will be allowed).
• More than 15 brain metastases on a volumetric T1 contrast MRI (voxels of 1mm3 or smaller) performed within the past 14 days, or more than 10 metastases in the case of a non-volumetric MRI.
• Prior allergic reaction to memantine, or hypersensitivity to any excipients of memantine.
• Current alcohol or drug abuse.
• Current use of NMDA antagonists, such as amantadine, ketamine, or dextromethorphan.
• Diagnosis of chronic liver disease/cirrhosis of the liver (e.g., Child-Pugh class B or C).
• Clinically significant untreated or uncontrolled cardiovascular conditions, and/or symptomatic cardiac dysfunction (i.e., unstable angina, congestive heart failure, myocardial infarction within the previous year, cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects, uncontrolled hypertension).
• Current active or uncontrolled urinary tract infections (UTI).
• History of epilepsy or seizures, and not currently taking anti-epileptic medication.
• Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patients safety, preclude safe administration of the planned protocol treatment, or would not permit the patient to be managed according to the protocol guidelines.
• Patients with architectural distortion of lateral ventricular systems which, in the opinion of the local investigator, makes hippocampal delineation challenging.

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
• All women will, by definition, be considered menopausal due to surgical removal of both ovaries prior to trial enrollment.
• Patients must have newly diagnosed, stage II-IV low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinoma) of the ovary or peritoneum. Tumors must be assessed for nuclear p53 staining.
• Appropriate stage for study entry based on the following diagnostic workup: 
  • History/physical examination within 14 days prior to registration; 
  • Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior to registration. 
• Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (< 1 cm diameter residual disease/nodule) or suboptimal residual disease (> 1 cm diameter residual disease/nodule) status allowed. 
• Patients must have undergone a bilateral salpingo-oophorectomy. 
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration .
• Patients must be within ≤ 8 weeks of primary cytoreductive surgery prior to initial randomization.
• Patients must be able to take per oral (P.O.) medications. 
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days prior to registration). 
• Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to registration).
• Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min (within 14 days prior to registration).
• Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN (within 14 days prior to registration).
• Alkaline phosphatase less than or equal to 2.5 x ULN (within 14 days prior to registration). 
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 
• Patients may not have received neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. 
• Patients may not have received previous hormonal therapy for the treatment of this disease. 
• Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy. 
• Patients with severe cardiac disease. 
• Myocardial infarction or unstable angina within 6 months prior to registration. 
• New York Heart Association (NYHA) Class II or greater congestive heart failure. 
• Patients with known central nervous system metastases.
• Patients with active or uncontrolled systemic infection. 
• Patients with ≥ Grade 2 baseline neuropathy. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
• Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
• All women will, by definition, be considered menopausal due to surgical removal of both ovaries prior to trial enrollment.
• Patients must have newly diagnosed, stage II-IV low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinoma) of the ovary or peritoneum. Tumors must be assessed for nuclear p53 staining.
• Appropriate stage for study entry based on the following diagnostic workup: 
  • History/physical examination within 14 days prior to registration; 
  • Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior to registration. 
• Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (< 1 cm diameter residual disease/nodule) or suboptimal residual disease (> 1 cm diameter residual disease/nodule) status allowed. 
• Patients must have undergone a bilateral salpingo-oophorectomy. 
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration .
• Patients must be within ≤ 8 weeks of primary cytoreductive surgery prior to initial randomization.
• Patients must be able to take per oral (P.O.) medications. 
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days prior to registration). 
• Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to registration).
• Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible if there is no hydronephrosis and the estimated creatinine clearance (CCr) is >= 30 ml/min (within 14 days prior to registration).
• Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN (within 14 days prior to registration).
• Alkaline phosphatase less than or equal to 2.5 x ULN (within 14 days prior to registration). 
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 
• Patients may not have received neoadjuvant chemotherapy or radiotherapy for the treatment of this disease. 
• Patients may not have received previous hormonal therapy for the treatment of this disease. 
• Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy. 
• Patients with severe cardiac disease. 
• Myocardial infarction or unstable angina within 6 months prior to registration. 
• New York Heart Association (NYHA) Class II or greater congestive heart failure. 
• Patients with known central nervous system metastases.
• Patients with active or uncontrolled systemic infection. 
• Patients with ≥ Grade 2 baseline neuropathy. 
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration.
• Note also that HIV testing is not required for eligibility for this protocol. This exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive.

• Understands the requirements of the study and provides written informed consent.
• prior to undergoing any study-related procedures.
• Subject is between the ages of 18 to 85 years old, inclusive.
• Has had and agrees to submit the results and images of a CT that shows some disease of the bowel or disease adjacent to bowel (e.g., peritoneal disease, carcinomatosis, omental caking or bowel inflammation), such that there is a reasonably high chance that the study CT scan could also show disease and which was:
  • conducted within 6 months prior to study entry;
  • conducted with IV and either positive or neutral oral contrast.
• Is willing and able to comply with protocol-specified CT scanning and visits to the clinic.
• Is able to lie flat with arms above head for 15 minutes and hold breath for 15 seconds.
• Is able to drink 1.2 liters of fluid within 45 minutes.
• Has good venous access as determined by the Investigator at screening.
• Is an outpatient who is able and willing to come to the clinic for study visits.

• Has any co-morbidity that the Investigator judges will interfere with their ability to complete the study or undergo a quality CT scan; e.g., high risk of aspiration.
• Has a history of or is currently suffering from a known gastrointestinal motility disorder; e.g., severe constipation / gastroparesis, achalasia, pseudo-obstruction, etc.
• Has symptoms of a possible current bowel obstruction.
• Has a moderate to high risk of current bowel perforation.
• Subject should not schedule a GI diagnostic surgery or hospitalization for any procedure until after the Study follow-up on Day 14 day. However, if at the time of study entry, the subject has pre-planned a surgery or hospitalization, it may be allowed at the discretion of the PI provided it does not take place until after the subject completes the Day 3 ± 2 days visit.
• Has a contraindication (i.e. allergy) to IV or Oral CT contrast.
• If of child-bearing potential, has a confirmed pregnancy or a high probability of pregnancy at the time of screening.
• Has received an investigational therapeutic or diagnostic agent or been treated with an investigational device within the 30 days prior to enrollment.

• Capable of giving signed informed consent.
• Refractory chronic cough (including unexplained chronic cough) for at least one year.
• Women of child-bearing potential must use a highly effective contraception method during the study and for at least 14 days after the last dose.

• Current smoker/vaper (all forms of smoking and inhaled substances, including , cannabis/tobacco smoke and nicotine vapors) or individuals who have given up smoking within the past 6 months, or those with > 20 pack-year smoking history.
• Diagnosis of Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, idiopathic pulmonary fibrosis or uncontrolled asthma.
• Respiratory tract infection within 4 weeks before screening.
• Laboratory confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection at screening.
• History of malignancy in the last 5 years.
• History of alcohol or drug abuse within the last 3 years.
• Has a positive serologic test for human immunodeficiency virus (HIV), hepatitis B virus surface antigen, or hepatitis C virus.
• Previous participation in a BLU-5937 trial.

Eligibility last updated 2/16/23. Questions regarding updates should be directed to the study team contact.

• Only patients who have undergone prior surgical/transcatheter repair (relief of right ventricular outflow tract obstruction, elimination of ventricular septal defect shunt and aorta-pulmonary collaterals) will be enrolled.

• None.

• Age ≥ 7 years.
• Biopsy confirmed newly diagnosed or recurrent WHO Grade II or Grade III malignant glioma.
• CT simulation, 18F-DOPA PET imaging, and standard of care pre-RT MRI scans to be performed at Mayo Clinic Rochester.
• Provide informed written consent.

• Patients diagnosed with WHO grade IV malignant glioma.
• Patients previously treated with radiation therapy.
• Unable to undergo MRI scans with contrast (e.g., cardiac pacemaker, defibrillator, kidney failure).
• Unable to undergo an 18F-DOPA PET scan (e.g., Parkinson’s Disease, taking anti-dopaminergic, or dopamine agonist medication or less than 6 half-lives from discontinuance of dopamine agonists.  Other potentially interfering drugs consist of: amoxapine, amphetamine, benztropine, buproprion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, paroxetine, citalopram, and sertraline).
• Any of the following:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.

Key

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

Eligibility last updated 9/15/22. Questions regarding updates should be directed to the study team contact.

• Adult females enrolled in the Mayo Clinic Biospecimen Resource for Breast Disease (IRB # 1815-04).
• Current ages 18-75 years.
• Have a prior diagnosis of stage 0-3 (in situ or invasive) breast cancer (BCS).
• Have completed active therapy (surgery, radiation, and/or chemotherapy) (8-30  months approximately) prior to provision of the samples).
• Age-matched females with no history of cancer (other than non-melanoma skin cancer) may be selected from the PRISM Study (IRB #18-002366 The Predicting Risk after Screening Mammogram (PRISM) Study) or the Mayo Clinic Breast Mammography practice.

• Male biological sex or gender.
• Pregnant females (insufficient #s, skewed estrogen levels).
• Unwilling to travel to Mayo Clinic Rochester to provide the blood and urine samples.

Inclusion Criteria 

• Male or female
• Age 40-70 years 
• Females of childbearing potential
  • Must have a negative pregnancy test prior to receiving the study drug 
  • Agree to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening to a period of 1 year following completion of the drug treatment cycle
  • Are defined as premenopausal and not surgically sterilized, or post-menopausal for fewer than 2 years
  • A urine pregnancy test will be performed prior to the administration of the study drug to confirm negative results
    • If the urine pregnancy test is positive, the study drug will not be administered 
    • Will be confirmed by a serum pregnancy test performed at a central clinical laboratory
  • Females becoming pregnant during the study will continue to be monitored for the duration of the study or completion of the pregnancy, whichever is longer
    • Monitoring will include perinatal and neonatal outcome
    • Any SAEs associated with pregnancy will be recorded
  • Females in the multiple-dose cohorts (M50 and M100) who become pregnant during the treatment cycle will not receive their remaining injections
• Chronic (> 3 months), unilaterally symptomatic, primary femorotibial knee osteoarthritis
• Radiographic medial and/or lateral femorotibial knee OA at least Kellgren-Lawrence grade 2 accompanied by definite joint space narrowing as agreed upon by two study co-investigators 
• Previous 6 week or longer trial of one of the following conservative treatments
  • Activity modification
  • Weight loss
  • Physical therapy
  • Anti-inflammatory medications or injection therapy (e.g. cortisone, hyaluronic acid/viscosupplement)
• Able to routinely walk without assistance (e.g. cane, walker) 
• Clinically stable target knee 
• No surgery planned in the target knee for at least 12 months following the last injection 
• Completed general physical evaluation with primary care provider within 12 months of enrollment 
• Fully understanding of the requirements of the study and willingness to comply with the treatment plan, including
  • Fat harvesting
  • Laboratory tests
  • Diagnostic imaging
  • Repeated knee injections/aspirations
  • Arthroscopic examination 
  • Follow-up visits and assessments 
• Can provide written informed consent and complete HIPAA documentation after the nature of the study is fully explained and prior to any study-related procedure

Exclusion Criteria

• Pregnant or nursing, or planning on becoming pregnant during the study period 
• Congenital or acquired malformation of the target knee resulting in significant deformity or leading to problems with the study treatment or analysis of the results 
• Significant malalignment on full length, standing radiographs 
• Orthopedic hardware or implantable devices anywhere in the body, other than dental 
• Surgery on the index knee within 1 year of study enrollment 
• Injections of any into the index knee within 3 months prior to study enrollment 
• Locking, catching, give-away or another major mechanical symptoms of the target knee
• Symptomatic patellofemoral arthritis or chondromalacia in the index knee
• History of intra-articular infection in the index knee 
• History of superficial infection in the index knee within 6 months of study enrollment, or evidence of current superficial infection affecting the index knee 
• History of falls requiring medical attention, or gait instability 
• Clinically significant abnormal hematology (complete blood count with differential), blood chemistry, or urinalysis screening laboratory results, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine, and CRP 
• Body mass index (BMI) > 40 kg/m2 
• Taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix)
• Taking herbal therapies or supplements within 4 weeks of enrollment or unwilling to avoid use of herbal therapies or supplements until at least 30 days following completion of the study drug treatment cycle (includes, but not limited to chondroitin sulfate, diacerein, n-glucosamine, piascledine, and capsaicin) 
• Taking non-steroidal anti-inflammatory medications (e.g. COX-2 inhibitors) without a stable dosing regimen for at least 4 weeks before baseline evaluation, or anticipating not remaining on a stable dose until at least 30 days following completion of the study drug treatment cycle
• Use of electrotherapy or acupuncture for OA, unless there is a stable regimen for at least 4 weeks before baseline assessment
• Taking anti-rheumatic disease medication (including methotrexate or other antimetabolites) within 3 months prior to study enrollment 
• On chronic, immunosuppressive transplant therapy or having a chronic, immunosuppressive state, including use of systemic steroids/corticosteroids 
• Current tobacco product use, including nicotine patch or other nicotine products
• Systemic inflammatory, rheumatological or connective tissue disorder including but not limited to rheumatoid arthritis, systemic sclerosis, system lupus erythematosus, and Ehlers-Danlos Syndrome 
• Rheumatological or inflammatory disease of the knee or chondrocalcinosis/calcium pyrophosphate disease (CPPD), hemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis, and synovial chondromatosis 
• Ongoing infectious disease, including but not limited to tuberculosis, HIV, hepatitis, and syphilis
• Clinically significant cardiovascular (e.g. history of myocardial infarction, congestive heart failure or uncontrolled hypertension > 90 mmHg diastolic and/or 180 mmHg systolic), neurologic (e.g. stroke, TIA) renal, hepatic, orthopedic (e.g. surgery on other weight bearing joints that will interfere with study, osteoporosis, acute lower body fractures), or endocrine disease (e.g. diabetes) 
• Vascular or neurological disorder affecting the either lower limb 
• History of cancer/malignancy with the exception of adequately treated basal cell or squamous cell carcinoma of the skin not associated with the target knee
• History of blood dyscrasia, including but not limited to anemia, thrombocytopenia, and monoclonal gammopathy 
• Participation in a study of an experimental drug or medical device within 3 months of study enrollment 
• Known allergy to local anesthetics or other components of the study drug 
• Any contraindication to MRI scan according to MRI guidelines, or unwillingness to undergo MRI procedures 
• History of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 30 days of study entry 
• Any illness or condition which, in the investigators' judgement will interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of the study results

• Male and female subjects 18 years of age and older.
• Have a primary diagnosis, or a high clinical suspicion, of cancer in the lung warranting surgery based on CT/PET or other imaging.
• Are scheduled to undergo surgical thoracoscopy for diagnostic wedge resection followed by anatomic lung resection.
• Female subjects of childbearing potential or less than 2 years postmenopausal agree to use an acceptable form of contraception from the time of signing informed consent until 30 days after study completion.
• Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments .

• Previous exposure to OTL38.
• Any medical condition that in the opinion of the investigators could potentially jeopardize the safety of the subject.
• History of anaphylactic reactions to folate, including synthetic folic acid (pteroylmonoglutamic acid) and contrast agents containing indocyanine green for near infrared imaging. Subjects with a medical history of 'idiopathic anaphylaxis' will require evaluation.
• History of allergy to any of the components of OTL38, including folic acid.
• A positive serum pregnancy test at Screening or a positive urine pregnancy test on the day of surgery or day of admission for female subjects of childbearing potential.
• Clinically significant abnormalities on electrocardiogram (ECG) at screening.
• Presence of any psychological, familial, sociological condition or geographical challenges potentially hampering compliance with the study protocol and follow-up schedule.
• Impaired renal function defined as eGFR < 50 mL/min/1.73m^2. Impaired liver function defined as values > 3 x the upper limit of normal (ULN) for alanine aminotransferase (ALT) or aspartate aminotransferase (AST), alkaline phosphatase (ALP), or > 2 x ULN for total bilirubin except in subjects with Gilbert's syndrome.
• Received an investigational agent in another investigational drug or vaccine trial within 30 days prior to the administration of study drug.
• Known sensitivity to fluorescent light.