• Females and males aged from ≥ 1 year to < 18 years old.
• Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) according to American Society of Hematology (ASH) 2011 guidelines.
• Platelets count < 30x10^9/L at the Baseline Visit.
• Voluntarily given written informed consent (provided by patient's parent or legal guardian) and assent (provided by patient [if age-appropriate per IRB (Institutional Review Board) requirements]).
• Females of childbearing potential have been using at least 1 acceptable form of birth control for a minimum of 30 days (or a minimum of 3 months for hormonal contraceptives) prior to the Screening visit, and must agree to use at least 1 acceptable method of contraception for 30 days after the last dose of PANZYGA. Acceptable methods of birth control for this study include: intrauterine device (IUD), hormonal contraception, male or female condom, spermicide gel, diaphragm, sponge, or cervical cap. Abstinence is not considered an acceptable method of birth control.
• Parent or legal guardian must agree and be willing to assist the participant attend study visits, and to follow all protocol requirements and instructions of the study doctor.

• Thrombocytopenia secondary to other diseases (such as Acquired Immunodeficiency Syndrome [AIDS] or systemic lupus erythematosus [SLE]), drug-related thrombocytopenia, or congenital thrombocytopenia.
• Administration of intravenous immunoglobulin (IGIV) or anti-D immunoglobulin within 3 weeks before enrollment.
• Administration of thrombopoietin receptor agonists when the dose has NOT been stable within 3 weeks before enrollment and a dosage change is planned before Day 32.
• Administration of oral immunosuppressants when the dose has NOT been stable during the preceding 2 months (2 weeks for long-term corticosteroid therapy) and a dosage change is planned before Day 32.
  • Note: topical agents and inhaled corticosteroid therapy use is permitted.
• Administration of long-term anti-prolific agents or attenuated androgen therapy when the dose has NOT been stable during the preceding 2 months and a dosage change is planned before Day 32.
• Non-responsive to previous treatment with IGIV or anti-D immunoglobulin.
• Evidence of an active major bleeding episode at Screening.
• Splenectomy in the previous 4 weeks or planned splenectomy throughout the study period.
• Evans syndrome (experiencing active disease with 2 out of 3 of the following: autoimmune thrombocytopenia, autoimmune hemolytic anemia, and/or autoimmune neutropenia).
• Known or suspected human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections.
• Emergency surgery in the previous 4 weeks.
• Severe liver and/or kidney disease (alanine aminotransferase [ALT] >3 x upper limit of normal (ULN), aspartate aminotransferase [AST] > 3 x upper limit of normal (ULN), and/or creatinine > 120 µmol/L).
• History of severe hypersensitivity to blood or plasma derived products, or any component of the PANZYGA.
• Known immunoglobulin A (IgA) deficiency and antibodies against IgA. History of, or suspected alcohol or drug abuse in the previous year.
• Females who are pregnant or nursing.
• Unable or unwilling to comply with the study protocol.
• Receipt of any other investigational medicinal product within 3 months before study entry.
• Risk factors* for thromboembolic events in whom the risks outweigh the potential benefit of PANZYGA treatment.
• Any other condition(s), that in the Investigator's opinion, make it undesirable for the patient to participate in the study or may interfere with protocol compliance.

*Risk factors include, but are not limited to:

• obesity, advanced age, hypertension, diabetes, a history of atherosclerosis/vascular disease or thrombotic events, hyperlipidemia, multiple cardiovascular risk factors, acquired or inherited thrombophilic disorders, prolonged periods of immobilization, severe hypovolemia, central venous catheterization, active malignancy and/or known or suspected hyperviscosity.

• Has participated in and completed the ADMIRE-CD II (NCT03279081) study (i.e., did not discontinue).

• Has been more than 3 months since the participant completed the ADMIRE-CD II study.

• Presence of inoperable malignant nonhilar extrahepatic biliary obstruction.
• Clinical symptoms of biliary obstruction.
• ≥ 18 years of age.
• Willing and able to provide informed consent.

• Participation in another investigational study within 90 days prior to consent.
• Strictures that could not be traversed by the delivery system.
• Perforation of any duct within the biliary tree.
• Presence of a biliary SEMS.
• Presence of any esophageal or duodenal stent.
• Contraindications to endoscopy.
• Sensitivity to any components of the stent or delivery system.
• Active hepatitis.
• Intrahepatic metastases that extensively involve both lobes of the liver.
• Life expectancy of < 3 months.

Key

• Are able and willing to comply with the Protocol and provide signed informed consent prior to any study-specific procedures.
• Are male or female ≥ 18 years old.
• Have a body mass index of ≥ 16.5 kg/m^2.
• Have findings consistent with bronchiectasis per computerized tomography (CT) (or high-resolution CT [HRCT]).
  • Note: A CT or HRCT that demonstrates the above criterion is required during Screening or the Screening Period unless such an examination has been performed within the last 5 years and meets the above criterion.
• Have microbiological evidence of pulmonary P. aeruginosa infection from a sputum sample within the last 24 months. Sputum cultures may be repeated on up to 3 occasions during the Screening Period to document P. aeruginosa presence if the initial sputum culture is negative.
• Are willing and able to provide an induced sputum sample at Screening or during the Screening Period and at designated time points during the study and are willing and able to provide a spontaneously expectorated or induced sputum at all other time points.
• Have ≥ 104 colony-forming units of P. aeruginosa per gram of induced sputum obtained at Screening or during the Screening Period. Up to 3 specimens may be collected to meet this criterion.
• Have forced expiratory volume (FEV1) ≥ 35% of predicted normal for age, gender, race, and height (using Global Lung Function Initiative standards) at Screening (regardless of the timing of the most recent prior administration of short-acting bronchodilator) or during the Screening Period.
• Have, at the Baseline Visit, stable lung function, as determined by the Investigator, provided that the FEV1 at the Baseline Visit has not decreased by more than 10% compared to the FEV1 measured at Screening or during the Screening Period.
• Have no acute infection or exacerbation of primary disease, as determined by the Investigator, prior to randomization and first dose of study drug.
• Are able to reproducibly perform spirometry per American Thoracic Society/European Respiratory Society Standards.
• Have past experience administering inhaled antibiotics and/or feel comfortable administering inhaled antibiotics and/or have a caregiver that is comfortable administering inhaled antibiotics to the subject.
• For Cohort A, have not received chronic inhaled antipseudomonal antibiotic regimen for at least 3 months prior to Visit 1. For Cohort B, have received chronic inhaled antipseudomonal antibiotic regimen for at least 3 months prior to Visit 1.
• Are able to comply with study visits and study procedures as judged by the Investigator.
• Have a negative serum pregnancy test at Screening and a negative urine pregnancy test at the Baseline Visit, with results known prior to randomization and first dose of study drug, if a woman of childbearing potential.
• Must agree to use a highly effective method of birth control (defined as those, alone or in combination, that result in a low failure rate [ie, less than 1% per year]) from Screening through 60 days following the last dose of study drug if female or female partner of male subjects, of childbearing potential; and
• Must agree to use barrier contraception (ie, condoms) from Day 1 through 60 days following the last dose of study drug if male. Male subjects must refrain from donating sperm throughout the study and until 60 days after the last dose of study drug.

• Have previously received 1 or more doses of AP-PA02 in any context, including, but not limited to, prior participation in study AP-PA02-101, prior enrollment in this study, or emergency use (with or without prior authorization).
• Have a history of lung transplantation.
• Have a history of primary or acquired immunodeficiency syndromes, including, but not limited to, hypogammaglobulinemia and common variable immunodeficiency.
• Have a history of cystic fibrosis.
• Have a history of α1-antitrypsin deficiency.
• Have a history of pulmonary malignancy (primary or metastatic) or any other malignancy requiring treatment (including, but not limited to, chemotherapy, radiation therapy, or immunotherapy) within 1 year prior to Screening or anticipated during the study period (Exceptions: Basal cell carcinoma of the skin and carcinoma in situ of the cervix surgically excised and assessed as definitely removed).
• Have, at Screening or during the Screening Period, either of the following findings:
  • A personal history or subject-reported family history of prolonged QT syndrome; or
  • Severe cardiovascular disease such as severe uncontrolled hypertension, unstable ischemic heart disease or cardiac arrhythmia and any other cardiac conditions that would confound the evaluation of safety in the opinion of the Investigator.
• Have a history of hemoptysis meeting either of the following criteria:
  • Within the 6 months prior to Screening, was hospitalized for management or evaluation of hemoptysis; or
  • Within the 3 months prior to Screening, had hemoptysis totaling greater than 30 mL in a single day.
• Have, within the 3 months prior to Screening, used supplemental oxygen during the day while at rest.
• Have, within the 3 months prior to Screening, lost more than 10% of their body weight.
• Have, within the 2 months prior to Screening, participated in any clinical study involving an investigational drug, an investigational device, or any systemic antibiotic.
• Note: For systemic drugs or antibiotics with a half-life > 12 days, the exclusion period is 5 half-lives.
• Have, within the 30 days prior to Screening, received any intravenous, intramuscular, or oral antipseudomonal antibiotic (Exception: Chronic oral macrolide treatment with a stable dose is permitted).
  • Note: Inhaled antibiotic use for chronic suppression of P. aeruginosa is acceptable for subjects enrolling in Cohort B.
• Have, within 30 days prior to Screening, had changes in either the treatment regimen or initiation of treatment with any of the following medications: oral macrolides (e.g., azithromycin, erythromycin, or clarithromycin), hypertonic saline, mucolytics, bronchodilator medications, or oral corticosteroids.
• Have, within the 30 days prior to Screening, received a course of any systemic antibiotics (by any route) for a new active infection at any site, unless assessed as fully resolved and not clinically significant by the Investigator with concurrence of the Medical Monitor.
• Are, at Screening or during the Screening Period, receiving treatment for active pulmonary infection due to any of the following pathogens: nontuberculous mycobacteria, Staphylococcus aureus, Burkholderia cepacia complex, Aspergillus species, or endemic mycoses.
• Are receiving treatment for allergic bronchopulmonary aspergillosis.
• Have, within 30 days prior to Screening, received either a systemic corticosteroid at a dose equivalent to > 20 mg/day of prednisone (including every other day dosing of > 40 mg equivalent) or any immunosuppressive medication or biologic for the treatment of inflammatory or autoimmune disease.
• Have history of AIDS (human immunodeficiency virus positive with AIDS-defining condition and/or CD4 count 3 × ULN or total bilirubin ≥ 2 × ULN at Screening.
  • Note: Abnormal laboratory results may be repeated once and only once at the discretion of the Investigator. Subjects with values outside the normal range may be permitted if the value is not clinically significant in the opinion of the Investigator with concurrence from the study Medical Monitor and/or Sponsor designee.
• Have, in the opinion of the Investigator, any acute or chronic medical, psychiatric, or behavioral condition or laboratory abnormality such that any of the following apply: the subject is considered not medically stable or in any other way not suitable for the study; participation in the study is not in the subject’s best interest, including, but not limited to, concern that participation in the study has the potential to put the subject at undue risk or to interfere with the results of the study or the outcome measures.

Eligibility last updated 12/20/23. Questions regarding updates should be directed to the study team contact.

• Males or females age ≥ 18 years
• Patient has non-metastatic, histologically confirmed primary or locoregionally recurrent estrogen receptor (ER) ≤ 10%, progesterone receptor (PR) ≤ 10%, and HER2-negative breast cancer (triple negative breast cancer [TNBC]) either using the baseline biopsy specimen or the post-neoadjuvant chemotherapy (NAC) residual surgical specimen and residual cancer burden (RCB)2 or RCB3, as defined by Symmans et al., 2007, and received neoadjuvant anthracycline and/or taxane-based chemotherapy OR patient has non-metastatic, histologically confirmed primary ER > 10% and/or PR > 10%, HER2-negative breast cancer with RCB3 and received neoadjuvant anthracycline and/or taxane-based chemotherapy OR patient has locoregionally recurrent TNBC or ER > 10% and/or PR > 10%, HER2-negative breast cancer.
  • Note: The RCB can be calculated at http://www3.mdanderson.org/ap/medcalc/index.cfm?pagename=jsconvert2
  • Note: Results from any CLIA-certified lab are acceptable for the purpose of determining study eligibility.
  • Note: For patients with primary breast cancer, there is no minimum number of neoadjuvant cycles required provided the patient received an anthracycline or taxane preoperatively. Patients with locoregionally recurrent breast cancer are not required to have received preoperative chemotherapy.
• Patient has undergone total mastectomy or wide local excision with axillary staging, and the margins of the resected wide local excision or mastectomy specimens are free of invasive tumor and ductal carcinoma in situ (DCIS) or patient has undergone axillary surgery for regionally recurrent breast cancer. Unresected axillary level III, internal mammary, and supraclavicular nodal disease is permitted.
  • Note: For patients who have undergone mastectomy, immediate reconstruction is allowed.
• Patients must have completed their final breast surgery including re-excision of margins for invasive cancer and DCIS, or received their last adjuvant chemotherapy infusion,  within 90 but not fewer than 21 days prior to registration unless patient received postoperative chemotherapy in which case patients must have completed their adjuvant chemotherapy within 90 days but not fewer than 28 days prior to registration. but no sooner than 21 days prior to the initiation of RT for surgery or 28 days for chemotherapy. Post-radiotherapy adjuvant systemic therapy (e.g. adjuvant capecitabine) may not be completed less than 21 days prior to the first fraction of RT or begin less than 28 days from the last fraction of RT.
• Patient must have recovered from surgery with the incision completely healed and no signs of infection prior to registration.
• Patients must be proceeding with breast/chest wall and regional nodal irradiation including internal mammary node treatment. BFor patients with bilateral breast cancer is permitted provided that , RT ismust be indicated and administered only to one side.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Willing to provide tissue and blood samples for correlative research:
  • Leukocytes ≥ 3,000/mcL;
  • Absolute neutrophil count ≥ 1,500/mcL;
  • Platelets ≥ 100,000/mcL;
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN;
  • Creatinine ≤ institutional ULN; OR
  • Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above ULN.
• 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.
• Negative urine or serum pregnancy test for individuals of childbearing potential.
  • Note: The effects of berzosertib on the developing human fetus are unknown. For this reason and because DNA-damage repair inhibitors as well as radiation used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 6 months after completion of M6620 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.  Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of berzosertib administration.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who have had chemotherapy within 4 weeks prior to entering the study.
• Prior RT to the ipsilateral chest wall or ipsilateral breast or thorax. Individuals with prior RT to the contralateral breast or chest wall are eligible.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and grade 1-2 taxane-induced neuropathy which will be permitted.
• Patients who are receiving any other investigational agents or concomitant anti-neoplastic treatment, except endocrine therapies and bisphosphonates which are permitted without restriction even during protocol treatment. Postoperative chemotherapy is allowed but must be discontinued >28 days prior to registration.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to berzosertib.
• Berzosertib is primarily metabolized by CYP3A4; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, and saquinavir) or inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided. Patients requiring any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study and for 14 days prior to enrollment are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with uncontrolled intercurrent illness. This includes but is not limited to, ongoing uncontrolled serious infection requiring IV antibiotics at the time of registration, symptomatic congestive heart failure, unstable angina pectoris, symptomatic/uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Active systemic lupus, scleroderma, or dermatomyositis with a CPK level above normal.
• Pregnant women are excluded from this study because berzosertib as a DNA damage repair inhibitor may have the potential for teratogenic or abortifacient. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with berzosertib, breastfeeding should be discontinued if the mother is treated with berzosertib.
• Patients with known hereditary syndromes predisposing to radiosensitivity such as Li Fraumeni syndrome and ataxia telangiectasia are excluded from the study. Patients with mutations in breast cancer predisposition genes such as BRCA1, BRCA2, PALB2, CHEK2, and ATM are eligible.
• Patients with a prior or concurrent malignancy, excluding non-melanoma skin cancers and non-invasive cancers whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.

• Age ≥ 18 years old.
• Histological confirmation of biopsy-proven non-Hodgkin lymphoma, excluding chronic lymphocytic leukemia, primary central nervous system (CNS) lymphoma and Burkitt's lymphoma.
  • Note: small lymphocytic lymphoma (SLL) is allowed.
• Patients with indolent non-Hodgkin lymphoma (NHL) must have had ≥ 1 regimen of rituximab-containing regimen.
  • Note: this includes follicular lymphoma (FL), marginal lymphoma and mucosa-associated lymphoid tissue (MALT).
• Patient with aggressive NHL must have received prior therapy
  •at a minimum:
  • Anti-CD20 monoclonal antibody unless tumor is CD20 negative; and
  • An anthracycline containing regimen;
  • Transformed FL must have had therapy for FL and be refractory to chemotherapy for DLBCL.
• Chemotherapy refractory disease in aggressive NHL is defined as:
  • Stable disease of ≤ 12 months or progressive disease as best response to most recent chemotherapy containing regimen;
  • Disease progression or recurrence ≤ 12 months of prior autologous stem cell transplantation (SCT).
• Patients with aggressive NHL must have failed autologous hematopoietic stem cell transplantation (HSCT), or are ineligible or not consenting to autologous HSCT.
• Patient must have at least 3 measurable lesions that are ≥ 1.5 cm in one dimension; one of the lesions must be ≥ 2.0 cm and is amenable to image-guided cryoablation and multiple vaccine injections as determined by interventional radiology and principal investigator (PI) (including tumors that can be safely accessed using imaging guidance and treated with minimal risk to adjacent structures).
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2.
• Absolute neutrophil count (ANC) ≥ 1000/mm^3.
• Absolute lymphocyte count ≥ 200/mm^3.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Platelet count ≥ 50,000/mm^3;
  • Hemoglobin ≥ 8.0 g/dL;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN), unless due to Gilbert's disease;
  • Aspartate transaminase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x ULN;
  • Creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min for subject with creatinine ˃ 1.5 x institutional ULN.
• Negative serum pregnancy test for women of childbearing potential ≤ 7 days prior to registration; Note: a second pregnancy test may be required ≤ 72 hours prior to receiving the first dose of study medication.
• Negative human immunodeficiency virus (HIV), hepatitis B and C, and tuberculosis (TB) test.
• Provide written informed consent.
• Willing to return to the enrolling institution for follow-up (during active treatment and active monitoring phase of the study).
• Ability to complete questionnaire(s) by themselves or with assistance.
• Willing to provide tissue and blood samples for research purposes.
• Willing to use adequate contraception while on the study and until 120 days after the last dose of study drug.

• Any of the following:
  • Pregnant women;
  • Nursing women.
• 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.
• Serious non-malignant disease such as active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations or other conditions which in the opinion of the investigator would compromise protocol objectives.
• Currently receiving or have received any other investigational agent considered as a treatment for the primary neoplasm ≤ 28 days or within 4 half-lives (whichever is shorter) of the agent prior to registration.
• History of other primary malignancy requiring systemic treatment within 6 months of protocol enrollment; patients must not be receiving chemotherapy or immunotherapy for another cancer; patients must not have another active malignancy requiring active treatment with the following acceptable EXCEPTIONS:
  • Basal cell carcinoma, squamous cell carcinoma, or melanoma of the skin that has undergone or will undergo potentially curative therapy;
  • In situ cervical cancer that has undergone or will undergo potentially curative therapy.
• Prior allogeneic bone marrow or peripheral blood stem cell transplantation.
• Prior autologous bone marrow or peripheral blood stem cell transplantation ≤ 100 days prior to registration or if recovery from the transplant is inadequate.
• Major surgery other than diagnostic surgery ≤ 4 weeks prior to registration.
• Prior chemotherapy or radiation therapy ≤ 2 weeks prior to registration or who has not recovered (i.e., to ≤ grade 1 or baseline) from an adverse event due to the previously administered therapy.
• History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine or any component of the formulation, including diphtheria toxoid.
• Active autoimmune disease such as Crohn's disease, rheumatoid arthritis, Sjogrens' disease, systemic lupus erythematosis, or similar conditions requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease/syndrome difficult to control in the past.
  • EXCEPTIONS:
    • Vitiligo or resolved childhood asthma/atopy;
    • Intermittent use of bronchodilators or local steroid injections;
    • Hypothyroidism stable on hormone replacement;
    • Diabetes stable with current management;
    • History of positive Coombs test but no evidence of hemolysis;
    • Psoriasis not requiring systemic treatment;
    • Conditions not expected to recur in the absence of an external trigger.
• Coagulopathy, including the use of Coumadin or heparin anticoagulants that cannot be discontinued for the cryoablation procedure.
  • NOTE: heparin for line patency without detectable lab abnormalities for coagulation will be allowed.
• Corticosteroid use ≤ 2 weeks prior to registration.
  • NOTE: patients must be off corticosteroids for at least 2 weeks prior to registration; this includes oral, IV, subcutaneous, or inhaled route of administration; patients on chronic corticosteroid for adrenal insufficiency or other reasons may enroll if they receive less than 10 mg/day of prednisone (or equivalent).
• Active CNS malignancy.
• Evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Received a live vaccine ≤ 30 days prior to registration.
• New York Heart Association classification III or IV cardiovascular disease or recent myocardial infarction or unstable angina pectoris or cardiac arrhythmia ≤ 30 days prior to registration.

• 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.

• Patient is 18 years of age or older.
• Patient has a diagnosis of migraine.
• Patient has been newly prescribed fremanezumab, non-fremanezumab CGRP-pathway targeting preventive migraine medications, or non-CGRP-pathway targeting preventive migraine medications.
• Patient has had a blood pressure and heart rate measurement recorded by a healthcare provider within 1 week prior to or on the day of informed consent.

• Patient has been previously treated with CGRP-pathway targeting preventive migraine medications.
• Per prior authorization criteria, patients will not receive approval for treatment with CGRP-pathway preventative migraine medications without prior treatment with non-CGRP medications.

Eligibility last updated 12/10/21. Questions regarding updates should be directed to the study team contact.

• Suspected glioma patient undergoing neurosurgery

• Patients without a diagnosis of glioma

• 18–65 years of age.
• Ability to provide written informed consent..
• Confirmed diagnosed with UC by colonoscopy and histology and suffering from mild to moderate UC as defined by MMDAI with score of 3-9.
• On a stable dose of aminosalicylate (i.e., no change in medication within 4 weeks of study enrollment) and not planning to initiate new medication other than the study drug.
• Fecal calprotectin level > 100 mg/g.
• For women of childbearing potential or men with a partner of childbearing potential, agree to use birth control methods during the study and at least 30 days after dosing (per FDA guidelines).
• For the expansion cohort, a flexible sigmoidoscopy is required, unless an endoscopy completed within 3 months from enrollment is available.

• Pregnancy, planned pregnancy, breastfeeding women.
• Evidence of severe UC disease (MMDAI score greater than or equal to 10).
• Evidence of any active or recent infection including chronic infectious disease such as chronic chest infection with bronchiectasis or sinusitis, or covid-19 infection in the past 3 months.
• Treatment with immunosuppressants or anti-cancer drugs; e.g., anti-TNF-α agents, anti-integrin agents, azathioprine or 6-MP, 6-thioguanine, methotrexate, ozanimod, tofacitinid, upadacitinib, tacrolimus, cyclophosphamide, or cyclosporine or any other therapy that is not an aminosalicylate within the last 3 months.
• Received an investigational drug within 3 months (or 5 half-lives, whichever is longer) before study entry.
• Use of steroidal drugs to treat UC (e.g., prednisone > 20 mg/day).
• Use of probiotics within the last 1 month.
• Treatment with systemic broad-spectrum antibiotics in the past 3 months.
• Major active systemic autoimmune disease other than UC.
• History of anaphylaxis or allergies to probiotics.
• History of alcohol or drug abuse within the past 2 years.
• History of stroke, or any cerebrovascular disease requiring medication/treatment.
• History of cancer, apart from successfully treated basal cell carcinoma or in situ carcinoma of the cervix >1 year prior to enrollment.
• Significant laboratory abnormalities, including liver transaminases (AST or ALT) > 1.5 X the upper limit of normal.
• Second degree higher heart block or clinically significant arrythmia.
• Any other clinically significant renal, hepatic, hematological or other disease or laboratory abnormality which, in the opinion of the investigator, would interfere with the conduct, the interpretation of the safety signals or results of the trial, or would place the subject at unacceptable risk.

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

Eligibility last updated  10/31/22. Questions regarding updates should be directed to the study team contact.

Recipient 

• Planned recipient of a first kidney allograft from an HLA-matched, living related donor. The donor and recipient must be HLA identical for both alleles at genetic loci HLA-A, HLA-B, and HLA-DRB1.
• Age ≥ 18 and ≤ 70 years at the time of providing informed consent.
• Single solid organ recipient (kidney only).
• ABO identical to the donor.  ABO compatible pairs that are not identical (e.g., ABO-O donor to ABO-A recipient) are not acceptable.
• Women of childbearing potential, including peri-menopausal women, should have a negative serum at Screening andor urine human chorionic gonadotropin (hCG) pregnancy test with a sensitivity < 50 mIU/mL at Screening and within 1 week prior to the kidney transplant surgery.  Women of childbearing potential, including peri-menopausal women, must receive contraceptive counseling and be willing and able to use effective contraception. The subject should use two chosen methods of contraception (e.g., hormonal contraceptives, intra-uterine device, diaphragm with spermicide, or condom with spermicide, male sterilization, or bilateral tubal occlusion) beginning no later than 4 weeks prior to starting MMF IS therapy, unless abstinence is the chosen method. She must be willing to continue contraceptive use during therapy and for at least 6 weeks after stopping MMF. In subjects for whom contraception is objectionable, complete abstinence (no vaginal penetration) for the duration of the study is required. Male subjects are required to use effective barrier contraception from Screening through at least 6 weeks after stopping MMF.   Able to receive oral medication.
• Able and willing to fully comply with all study procedures and restrictions.
• Acknowledgment of the expectation to participate in a separate, prospective, multi-year, longterm follow-up study (MDR-101-MLK-Plus) at the end of the current study (MDR-101-MLK).

Recipient Exclusion Criteria:

• Underlying kidney disease with a high risk of disease recurrence in the transplanted kidney, including:
  • Focal segmental glomerulosclerosis (FSGS);
  • Type I or II membranoproliferative glomerulonephritis;
  • Hemolytic-uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP).
• History of clinically important genitourinary tract dysfunction.
• History of undergoing a prior hematopoietic cell transplant, organ transplant, any cell therapy, or any gene therapy.
• Baseline positive donor-specific anti-HLA antibody testing (DSA).
• History of HUS, atypical HUS, or TTP.
• Women who are pregnant or breastfeeding.
• Is taking IS therapy [eg, glucocorticoids, cyclosporine, mycophenolate, tumor necrosis factor (TNF) inhibitors] for multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, or other acute or chronic condition.
• History of prior treatment with rabbit-derived ATG or a known allergy to rabbit proteins.
• History of cancer with the exception of non-melanoma skin cancer and adequately treated breast, prostate, or cervical in situ lesions (i.e., locally confined, non-invasive tumors) within 5 years prior to Screening.
• Has an active serious infection not controlled by oral or IV antibiotics or antifungals.
• Leukopenia (WBC count < 3,000/μL) or thrombocytopenia (platelet count < 100,000/μL).
• Serological or nucleic acid test (NAT) evidence of human immunodeficiency virus (HIV)-1 or HIV-2.
• Evidence of prior hepatitis B (HBV) infection as evaluated by hepatitis B surface antigen (HBsAg), total hepatitis B core antibody [(anti-HBc Immunoglobulin M (IgM) and Immunoglobulin G (IgG)] and hepatitis B surface antibody (anti-HBsAb), or exhibiting a positive HBV polymerase chain reaction (PCR) result.
• Evidence of prior hepatitis C (HCV) infection as evaluated by positive anti-HCV antibodies and a positive serum HCV ribonucleic acid (RNA) PCR. Participants with positive HCV antibodies but undetectable serum HCV RNA may be considered for eligibility. Participants with negative anti-HCV antibodies but unexplained liver enzyme abnormalities must undergo a quantitative serum RNA assay to rule out false negative HCV serologies.  Known hypersensitivity to dimethyl sulfoxide (DMSO), dextran, murine (mouse) proteins, or iron dextran.
• Has any medical condition or any circumstance that in the opinion of the Investigator places the subject at an unacceptably high risk for toxicities, or would significantly interfere with the subject’s protocol compliance or put the subject at increased risk.
• Has been exposed to a live vaccine, approved or investigational, within the 30 days prior to the scheduled kidney transplantation.
• Participation in any other study of an investigational device, small molecule medication, biologic medication, or other agent within 30 days or 5 half-lives of the investigational product, whichever is longer, before MDR-101-MLK study enrollment and until completion of the final study followup visit.

Donor

• HLA-matched first-degree (parent, child or sibling) or second-degree (child of a sibling, half sibling) relative of the prospective recipient participant. The donor and recipient must be HLA identical for both alleles at genetic loci HLA-A, HLA-B, and HLA-DRB1.
• Age ≥ 18 and ≤ 7065 years at the time of providing informed consent.
• Prepared to be a living related kidney donor, and capable, as defined below, of undergoing G-CSF mobilization and apheresis for donation of hematopoietic cells:
  • Weight ≥ 50 kg, hematocrit ≥ 38%, and platelet count ≥ 110,000/μL;
  • Adequate peripheral venous access for apheresis. A central venous catheter may be placed with appropriate informed consent from the prospective donor.
• Women of childbearing potential, including peri-menopausal women, should have a negative serum at Screening andor urine human chorionic gonadotropin (hCG) pregnancy test with a sensitivity < 50 mIU/mL at Screening and within 1 week prior to the kidney transplant surgery.
• Able and willing to fully comply with all study procedures and restrictions.
• Meets institutional selection criteria for kidney donation and apheresis of mobilized peripheral blood stem cells (PBSCs).
• Able to understand and provide written, signed, and dated informed consent to participate in the study.

Donor

• Known sensitivity to filgrastim or to E. coli-derived recombinant protein products.
• History of autoimmune disorders, including rheumatic diseases and unsuccessfully treated thyroid disorders.
• History of undergoing a prior hematopoietic cell transplant, organ transplant, any cell therapy, or any gene therapy.
• History of type 1 or type 2 diabetes mellitus.
• History of blood product donation to prospective recipient participant.
• Pregnant or breastfeeding.
• History of deep vein thrombosis or pulmonary embolism.
• History of iritis or episcleritis.
• Current treatment with lithium.
• Taking IS therapy (e.g., glucocorticoids, CsA, Tac, mycophenolate, or TNF inhibitors).
• Positive Hemoglobin-Solubility (e.g., SickleDex™ or equivalent) test.
• Tests confirmed positive for HIV-1/2, human T-cell lymphotropic virus (HTLV)-I/II, West Nile Virus, HBV (as evaluated by HBsAG, anti-HBcIgM and IgG, and anti-HBsAg, or exhibiting a positive HBV PCR result), HCV (as evaluated by positive anti-HCV antibodies and a positive serum HCV RNA PCR; positive HCV antibodies but undetectable serum HCV RNA may be considered for eligibility), T. cruzi, or syphilis. Cytomegalovirus (CMV)-positive donors will not be excluded but the subject and Investigator will be notified of the CMV-positive status.  Epstein-Barr Virus (EBV)-positive donors will be excluded if the prospective transplant recipient is EBV naive.
• History of infection with Zika virus (ZIKV) in the past 6 months, as evidenced by a clinical diagnosis and/or a positive test for ZIKV. Each transplant center may use local screeening practices to screen and exclude donors with geographic (residence/travel) risk for ZIKV in the donor or the donor’s sexual partner(s).
• History of myeloid leukemia, myeloproliferative disease (e.g., polycythemia vera, essential thrombocythemia, myelofibrosis), or prior hematopoietic cell transplant.
• Participation in any other study of an investigational device, small molecule medication, biologic medication, or other agent within the 30 days or 5 half-lives of the investigational product, whichever is longer, before MDR-101-MLK study enrollment and until completion of the final donor study follow-up visit.
• Has any condition or circumstance, which in the opinion of the Investigator would significantly interfere with the subject’s protocol compliance or put the subject at increased risk.

• 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.

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

Eligibility last updated 9/19/22. Questions regarding updates should be directed to the study team contact.

• 40 nondiabetic subjects will be recruited.  
• After approval from the Mayo Clinic Institutional Review Board, the Mayo Clinic Biobank will genotype individuals at rs3765467:
  • recruit subjects so that 20 will have the AA genotype at rs3765467;
  • remainder will have the GG genotype.
• Individuals encompassing the age span of 25-65 years.

• Individuals under 25 and over 65 years of age.

Key

• 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.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

• Participant must be ≥ 18 years of age, at the time of signing the informed consent.
• Participants who are ≥ 40 kg at Screening Visit 1.
• Participants who have a documented diagnosis of HES prior to Visit 2. HES diagnosis is based on:
  • blood eosinophilia of > 1500 eosinophils/µL on at least 2 occasions at ≥ 1-month interval, without a discernible non-haematological secondary cause; and
  • signs or symptoms of organ involvement and/or dysfunction that can be directly related to eosinophilia.
• Flare history: A history of 2 or more HES flares within the past 12 months prior to Visit 1. Historical HES flares are defined as documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an addition or escalation in OCS or cytotoxic/immunosuppressive therapy. At least one HES flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
  • Is a woman of non-childbearing potential (WONCBP); OR
  • Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, from at least 14 days prior to the first dose of study intervention until at least 30 weeks after the last administered dose of study intervention. The Investigator should evaluate the potential for contraceptive method failure (e.g., non-compliance, recently initiated) in relationship to the first dose of study intervention;
  • A WOCBP must have a negative highly sensitive serum pregnancy test at Screening Visit 1 and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention;
  • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies;
  • The Investigator should evaluate the potential for contraceptive method failure (e.g., non-compliance, recently initiated in relationship to the first dose of study intervention;
  • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

• HES disease manifestations which in the opinion of the Investigator may put the participant at unacceptable risk from study participation or confound interpretation of efficacy or safety data. Specific consideration should be given to the participant’s ability to comply with protocol requirements, including the list of prohibited therapies; exclusion criteria no. 14
  •16.
• Participants with chronic or ongoing active infections requiring systemic treatment.
• Participants with a pre-existing parasitic infestation within 6 months prior to Visit 1.
• Participants with a known immunodeficiency (e.g., Human Immunodeficiency Virus [HIV]), other than that explained by the use of OCS or other therapy taken for HES.
• Participants with a history of or current lymphoma.
• Participants with current malignancy or previous history of cancer in remission for less than 5 years prior to Visit 1. Participants that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded.
• Participants with a haematologic malignancy with hypereosinophilia in which HES is not the primary diagnosis; e.g., chronic myeloid leukaemia, myelodysplastic syndrome, chronic eosinophilic leukaemia-not otherwise specified.
• Cirrhosis or current unstable liver or biliary disease per Investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice.
  • NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C) are acceptable if participant otherwise meets entry criteria.
• Participants who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment.
• Participants with current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at Screening will be evaluated and current vasculitis must be excluded prior to randomization.
• Eosinophilia of unknown significance: Hypereosinophila with no clinical symptoms and/or proof of organ dysfunction.
• Clinical diagnosis of EGPA.
• Participants that, according to the Investigator's medical judgment, are likely to have active COVID-19 infection should be excluded.
• Participants with known COVID-19 positive contacts within the past 14 days must be excluded for at least 14 days following the exposure during which the participant must remain symptom-free.
• Participants who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, cardiac or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment.
• Participants with an allergy/ intolerance to a monoclonal antibody or biologic, or any of the excipients of the investigational product.
• Monoclonal antibodies (mAbs) targeting IL-5/5R: Participants who have a previous documented failure with anti-IL-5/5R therapy.
• Participants who have received mAb within 30 days or 5 half-lives, whichever is longer, prior to Visit 1. If a participant has been treated with and responsive to biologics for HES, the participant should not stop the treatment for study eligibility purpose.
• Non-oral systemic corticosteroids: Participants who have received intravenous, intramuscular, or subcutaneous corticosteroids within 4-weeks prior to Visit 2.
• Participants who have received treatment with an investigational agent within 30 days or 5 drug half-lives whichever is longer, prior to Visit 1. The term “investigational” applies to any drug not approved for sale in the country in which it is being used or investigational formulations of marketed products.
• Participants who are currently participating in any other interventional clinical study.
  • Note: Any COVID-19 vaccine approved by local government is permitted. Experimental COVID-19 vaccines are not permitted.
• Participants who test positive for the FIP1L1-PDGFRα fusion gene. Blood sampling is required for all participants at Screening (Visit 1) for this test unless the documented result is available.
• ECG Assessment: QTcF ≥ 450 msec or QTcF ≥ 480 msec for participants with Bundle Branch Block at Screening Visit 1.
• Participants who are not responsive to OCS based on clinical response or blood eosinophil counts in the opinion of the Investigator.
• A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
• Participants who are pregnant or breastfeeding.
• Participants must not be randomized if they plan to become pregnant during the time of study participation.
• Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.

- Sedation for invasive mechanical ventilation immediately prior to Baseline for > 72 hours (patients who have been extubated for at least 24 hours and subsequently re-intubated will have sedation for invasive mechanical ventilation starting from when they were re-intubated); 

- Severe neurological condition that causes the patient to lack ability to participate in the study (i.e., unable to be assessed for RASS and Critical Care Pain Observation Tool), including, but not restricted to, patients with acute stroke, severe head trauma, meningitis, suspected of having elevated intracranial pressure (ICP), or the need for ICP monitoring;

- Ventilator tidal volume 1000 mL at Baseline;

- Need for extracorporeal membrane oxygenation, extracorporeal carbon dioxide removal, high frequency oscillation ventilation, or high frequency percussive ventilation at Screening;

- Comfort care only (end of life care);

Contraindication to propofol or isoflurane, including:

• Known or suspected personal or family history of malignant hyperthermia (MH) or high risk for MH or acute drug-induced muscle injury (e.g., muscular dystrophies);
• Severe hemodynamic compromise, defined as the need for norepinephrine ≥ 0.3 mcg/kg/min (or equivalent vasopressor dose) to maintain blood pressure within acceptable range, assumed to be mean arterial pressure ≥ 65 mmHg unless prescribed clinically; or
• Allergy to isoflurane or propofol, or have propofol infusion syndrome.

-  History of ventricular tachycardia/Long QT Syndrome;

-  Requirement of intravenous (IV) benzodiazepine or barbiturate administration for seizures or dependencies, including alcohol withdrawal;

- Neuromuscular disease that impairs spontaneous ventilation (eg, C5 or higher spinal cord injury, amyotrophic lateral sclerosis, etc);

- Concurrent enrollment in another study that, in the Investigator’s opinion, would impact the patient’s safety or assessments of this study;

- Participation in other study involving investigational drug(s) or devices(s) within 30 days prior to Randomization;

- Previous randomization or receipt of treatment in this study or in SED004;

- Anticipated requirement of treatment with continuous infusion of a neuromuscular blocking agent for > 4 hours;

- Female patients who are pregnant or breast-feeding;

- Imperative need for continuous active humidification through mechanical ventilation circuit;

- Attending physician’s refusal to include the patient; or

- Inability to obtain informed consent.

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

Eligibility last updated 12/15/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria:  

• Women age ≥ 18 years.
• Biopsy-proven high-grade endometrial cancer.
• Biopsy histology is Grade 3 endometrioid, serous, clear cell, poorly differentiated, or undifferentiated.
• Scheduled to undergo hysterectomy at Mayo Clinic.
• Willing to complete pre-op blood sample and follow-up serial blood samples post-operatively.
• Willing and able to provide signed informed consent.

Exclusion Criteria: 

• Biopsy histology is Grade 1 or Grade 2 endometrioid.
• Change in planned surgical procedure such that hysterectomy is not performed at Mayo Clinic.
• Pre-op blood sample is not obtained.
• Tumor quantity or cell viability expected to not be sufficient for the study analyses.

Inclusion Criteria

• Age ≥ 18 years old
• Diagnosis of Brain Metastases
  • Presence of presumed brain metastases from an extra-cerebral tumor site (e.g. lung, breast, prostate, etc.).
  • Note: Dural based metastases (e.g. commonly seen in breast cancer) are eligible.
• Size of Brain Metastases
  • At least one intact metastasis (not previously treated with radiosurgery) must measure > 2.0 cm and < 4.0 cm in maximal extent on the contrasted pre-treatment MRI brain scan obtained ≤ 28 days prior to registration.
  • If the largest lesion measures ≥ 2.0 to < 4.0 cm in maximal extent the patient will be randomized.
• Able to undergo contrast enhanced MRI Brain
• Negative urine or serum pregnancy test completed ≤7 days prior to registration, for women of childbearing potential only
• Patient willing and able to provide written informed consent
• Karnofsky Performance Status (KPS) ≥ 50
• ECOG Performance Score of (PS) ≥ 2
• Past radiosurgery or resection is allowed as long as no definitive evidence of progression in these locations.
  • Note: Repeat radiosurgery to the same location/lesion is not allowed on this protocol.

Exclusion Criteria

• Any patient who has received previous whole brain radiation
• Any brain metastasis that is located in the brainstem measuring ≥ 2.0 cm in maximal extent.
• Any patient with definitive evidence of leptomeningeal metastasis (LMD).

NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator’s discretion based on level of clinical suspicion.{Kim, 2017 #2840}

• Any patient with an intact brain metastasis measuring > 4.0 cm

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

Eligibility last updated 7/28/22. Questions regarding updates should be directed to the study team contact.

• Study subjects 41 years of age and older 
• Subjects will be recruited through the Mayo Clinic ADRC and enrolled in existing research protocols
• Healthy Volunteers 18 years of age or older

• Subjects and a suitable informant will be interviewed by nurse clinicians who will complete a modified Clinical Dementia Rating (CDR) and Mayo Sleep Questionnaire to assess for REM sleep behavior disorder (RBD) in aging and dementia cohorts
• RBD is highly associated with an underlying synucleinopathy and is therefore used as an exclusionary criterion in this study of typical AD

• Greater than 18 years of age.
• Presenting for cardiac surgery at Mayo Clinic in Rochester, Minnesota.
• Scheduled to undergo cardiac surgery with the use of cardiopulmonary bypass involving myectomy or valve replacement/repair.

Exclusion Criteria:

• Cases involving planned coronary artery bypass grafting (CABG).
• Cases requiring circulatory arrest.
• Active infection or sepsis.
• Severe hepatic disease or ascites.
• Pre-operative renal dysfunction requiring dialysis.
• Preoperative midodrine, oral steroid, or intravenous steroid use. Inhaled steroids are not an exclusion criteria.
• Pregnancy and glucose-6-phosphate dehydrogenase (G6PD) deficiency.