Subjects who meet all the following criteria will be eligible for the study:

• Women and men between 18 and 85 years of age.
• Have a diagnosis of interstitial lung disease (ILD) according to the American Thoracic Society Guidelines.
• Have a chronic cough for at least 3 months prior to the screening visit.
• Patients should be on a stable dose of ILD-directed therapies for 3 months prior to enrollment and will be allowed to continue their ILD-directed therapies. These include –but are not limited to- corticosteroids, immunosuppressing agents such as azathioprine and mycophenolate, as well as antifibrotic medications including nintedanib and pirfenidone. Additional corticosteroids and adjustment of ILD-directed therapy doses is permitted if deemed appropriate by the treating physician.
• Have a score of ≥ 40mm on the Cough Severity VAS at Screening..
• Women of child-bearing potential must use 2 forms of acceptable birth control and make no donation of eggs from Screening through the end of the 8-week study period. Acceptable birth control methods include established use of oral, injected, or implanted hormonal methods of contraception; intrauterine device (IUD) or intrauterine system (IUS); tubal ligation; or male sterilization. Double-barrier method (diaphragm for female subject and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control. When concordant with the preferred lifestyle of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
• Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control, 1 of which must be a barrier method, and make no donation of sperm from Screening until 3 months after the last dose of study drug at the end of 8 weeks.
• Have provided written informed consent.
• Are willing and able to comply with all aspects of the protocol.

Subjects are NOT eligible for this study if they meet any of the following criteria:

• Current smoker (cigarettes, e-cigarettes or marijuana) or former smokers who have smoked within the past 12 months.
• Former smokers with > 20 pack-year history of smoking.
• Ongoing treatment with an ACE-inhibitor that is considered as the potential cause of a subject’s cough or requiring treatment with an ACE-inhibitor during the study or within 12 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
• History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Screening/Baseline Visit (Day -14 to Day 0).
• History of opioid use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of opioids for other indications (for example, to treat pain) is permitted.
• History of baclofen use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of baclofen for other indications (for example, to treat spasticity) is permitted.
• Presence of an untreated or undertreated cause (other than ILD) for the patient’s chronic cough (per ACCP guidelines). e.g. uncontrolled asthma, GERD or post-nasal drainage that could potentially explain the patient’s chronic cough.
• Requiring concomitant therapy with prohibited medications.
• Treatment with any pharmaceutical or biological investigational therapy (excluding COVID vaccination and COVID related monoclonal antibody therapy).
• Participation in another clinical trial that does not allow co-enrollment within 4 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
• Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN) during screening.
• Serum creatinine < 30 mL/min, hemodialysis or peritoneal dialysis.
• Advanced liver disease as defined by the presence of cirrhosis and/or signs of portal hypertension.
• History of previous hypersensitivity or intolerance to Duloxetine & Amitriptyline (patients who have previously been on either amitriptyline or duloxetine for chronic cough or other reasons and have tolerated the medication will be offered participation regardless of previous response to therapy).
• Currently pregnant or breastfeeding female subject.
• Presence of any medical condition or disability that the investigators believe could interfere with the assessment of safety or efficacy in this trial or compromise the safety of the subject.
• Planned or anticipated major surgical procedure or other activity that would interfere with the subject’s ability to comply with protocol-mandated assessments (e.g., extended travel) during the subject’s participation in the study. 
• Currently taking either another SSRI, SNRI or MAO inhibitor which the patient cannot safely discontinue at least 2 weeks prior to the screening period.

Eligibility last updated 6/3/22. Questions regarding updates should be directed to the study team contact.

• Signed Informed Consent Form.
• Age 18-75 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Active or active/chronic ISN/RPS 2003 Class III or IV proliferative LN by renal biopsy performed in the 6 months prior to screening or during screening:
  • One or more active glomerular lesions must be present;
  • Class V disease may be present in addition to Class III or IV;
  • The local biopsy report will be used to determine eligibility.
• SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria, which are met by the presence of Class III or IV LN (above) and current or past positive antinuclear antibody (ANA) Positive ANA is defined by ANA at a titer of ≥ 1:80 on HEp-2 cells or an equivalent positive ANA test at least once. UPCR ≥ 1 on a 24-hour collection at screening
• Receipt of at least one dose of pulse methylprednisolone IV (≥ 250 mg) or equivalent for treatment of the current episode of active LN during the 6 months prior to screening or during screening, or to be given on Day 1 prior to the first infusion.
  • A maximum of 3 g methylprednisolone IV or equivalent during the 4 weeks prior to screening or during screening is allowed.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraception, as defined below: Women must remain abstinent or use two reliable methods of contraception, including at least one method with a failure rate of < 1% per year, during study treatment and for 18 months after the final dose of obinutuzumab or placebo and 6 weeks after the final dose of MMF. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation; male sterilization; established, proper use of hormonal contraceptives that inhibit ovulation; hormone-releasing intrauterine devices; and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method used by the female partner that together result in a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of MMF. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or placebo or within 6 weeks after the final dose of MMF.
• Women of childbearing potential, including those who have had a tubal ligation, must have a negative urine pregnancy test at screening. Positive test results will be confirmed with a serum pregnancy test. Severe renal impairment, as defined by eGFR < 30 mL/min/1.73 m^2 (as estimated using the CKD-EPI equation) or the need for dialysis or renal transplantation.
• Sclerosis in > 50% of glomeruli on renal biopsy.
• Presence of rapidly progressive glomerulonephritis, defined by any of the following:
  • Crescent formation in ≥ 50% of glomeruli assessed on renal biopsy;
  • Sustained doubling of serum creatinine during the 2 months prior to screening;
  • The investigator’s opinion that the patient has rapidly progressive glomerulonephritis.
• Receipt of any of the following excluded therapies:
  • Any anti-CD20 therapy such as rituximab, ocrelizumab, or ofatumumab less than 9 months prior to screening or during screening;
  • If an anti-CD20 therapy has been received between 9 and 12 months prior to screening, the peripheral CD19+ B-cell count must be ≥ 25 cells/µL;
  • Cyclophosphamide, tacrolimus, ciclosporin, or voclosporin during the 2 months prior to screening or during screening;
  • Any biologic therapy (other than anti-CD20) such as, but not limited to, belimumab, ustekinumab, anifrolumab, secukinumab, or atacicept during the 2 months prior to screening or during screening;
  • Oral inhibitors of Janus-associated kinase (JAK), Bruton’s tyrosine kinase (BTK), or tyrosine kinase 2 (TYK2), including baricitinib, tofacitinib, upadacitinib, filgotinib, ibrutinib, or fenebrutinib or any investigational agent during the 2 months prior to screening or during screening;
  • Any live vaccine during the 28 days prior to screening or during screening.
• Severe, active central nervous system SLE, including retinitis, poorly controlled seizure disorder, acute confusional state, myelitis, stroke, cerebellar ataxia, or dementia.
• High risk for clinically significant bleeding or any condition requiring plasmapheresis, intravenous immunoglobulin, or acute blood product transfusions.
• Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation.
• HIV infection:
  • For patients with unknown HIV status, HIV testing will be performed at screening if required by local regulations.
• Tuberculosis (TB) infection:
  • Testing for latent TB will be performed at screening if required by local regulations or in accordance with local clinical practice;
  • Latent TB after completion of appropriate treatment is not exclusionary.
• Active infection of any kind, excluding fungal infection of the nail beds.
• Any major episode of infection that also fulfills any of the following criteria:
  • Requires hospitalization during the 8 weeks prior to screening or during screening;
  • Requires treatment with IV antibiotics or anti-infectives during the 8 weeks prior to screening or during screening;
  • Requires treatment with oral antibiotics or anti-infectives during the 2 weeks prior to screening or during screening:
    • Antibiotics or anti-infectives given in the absence of a major episode of infection are not exclusionary.
• History of serious recurrent or chronic infection.
• History of progressive multifocal leukoencephalopathy (PML).
• History of cancer, including solid tumors, hematological malignancies, and carcinoma in situ, within the past 5 years:
  • Patients with non-melanomatous carcinomas of the skin that have been treated or excised and have resolved are eligible.
• Major surgery requiring hospitalization during the 4 weeks prior to screening or during screening.
• Current alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening or during screening.
• Intolerance or contraindication to study therapies, including any of the following:
  • History of severe allergic or anaphylactic reactions to monoclonal antibodies or known hypersensitivity to any component of the obinutuzumab infusion;
  • Intolerance or contraindication to oral or IV corticosteroids;
  • Intolerance to MMF;
  • Lack of peripheral venous access.
• Any of the following laboratory parameters:
  • AST or ALT > 2.5 x ULN;
  • Amylase or lipase > 2 x ULN;
  • Neutrophils < 1.5 x10^3 /µL;
  • Positive hepatitis B surface antigen (HBsAg);
  • Patients who are HBsAg negative and hepatitis B core antibody (HBcAb) positive with no detectable hepatitis B virus (HBV) DNA are eligible but will require monthly HBV DNA monitoring until 12 months after the last dose of obinutuzumab or placebo.
• Positive hepatitis C serology Patients with positive hepatitis C antibody test result with no detectable hepatitis C virus (HCV) RNA at least 6 months after completion of antiviral therapy are eligible but will require monthly HCV RNA monitoring until 12 months after the last dose of obinutuzumab or placebo.
• Hemoglobin < 7 g/dL, unless caused by autoimmune hemolytic anemia resulting from SLE.
• Platelet count < 25,000/µL.
• Positive serum human chorionic gonadotropin measured at screening.

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

• Voluntary and valid written informed consent to participate in the trial provided by the patient before any trial related procedures are performed.
• Male or female patient, ≥ 18 years at screening.
• Diagnosis of PLD (associated with ADPKD or isolated as in ADPLD) as defined by htTLV ≥ 2500 mL/m at screening.
• Presence of at least 1 of the following PLD-related symptoms within 2 weeks before screening: bloating, fullness in abdomen, lack of appetite, feeling full quickly after beginning to eat, acid reflux, nausea, rib cage pain or pressure, pain in side, abdominal pain, back pain, shortness of breath after physical exertion, limited in mobility, concern about abdomen getting larger, dissatisfied by the size of abdomen.
• Not a candidate for, or not willing to undergo, surgical intervention for hepatic cysts during the trial.
• Female patients of childbearing potential must be willing to use an acceptable method of contraception from screening and during the entire trial.
• Male patients must be willing to use condom as method of contraception from screening and throughout the trial unless they have been sterilized by vasectomy (with an appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).

• Surgical intervention for PLD within 3 months before screening.
• Treatment with an SSA within 3 months before screening.
• Non-responsive to previous treatment of PLD with an SSA as per the Investigator’s assessment.
• Cholelithiasis within 3 months before screening or previous medical history of cholelithiasis induced by SSAs unless treated with cholecystectomy.
• Presence of extrahepatic cysts that, in the Investigator’s opinion, may prevent the patient from safely participating in the trial.
• Severe kidney disease, as defined by estimated glomerular filtration rate (eGFR) 160 mmHg and/or diastolic blood pressure of >100 mmHg at screening.
• Severe liver disease defined as liver cirrhosis of Child-Pugh class C.
• Use of oral contraceptives or estrogen supplementation within 3 months before screening.
• Poorly controlled diabetes (hemoglobin A1c ≥ 10%) at screening.
• Patients with a known history of hypothyroidism, unless they have been on adequate and stable replacement thyroid hormone therapy for at least 3 months before the first dose of the IMP.
• Uncontrolled hypertension defined by a systolic blood pressure of > 160 mmHg and/or diastolic blood pressure of > 100 mmHg at screening
• History of significant cardiac disease or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the trial, such as uncontrolled or significant cardiac disease, including any of the following:
  • History of myocardial infarction, angina pectoris or coronary artery bypass graft within 6 months before screening;
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block or high-grade atrioventricular block (e.g., bifascicular block, Mobitz type II and third-degree atrioventricular block);
  • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
  • Risk factors for Torsades de Pointes including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure or history of clinically significant/symptomatic bradycardia;
  • Treatment with concomitant medication(s) with a "Known risk of Torsades de Pointes" per www.crediblemeds.org that cannot be discontinued or replaced by safe alternative medication at least 5 half-lives or 7 days (whichever is longer) before the first dose of IMP;
  • Patients with a baseline QTc interval corrected by Fridericia's formula (QTcF) > 450 msec for males and > 470 msec for females at screening.
• Patients with vascular compromise, including, but not limited to, mesenteric thrombosis, portal hypertension and thrombocytopenia (platelet counts less than 100 x 10^9 /L).
• Pregnant, lactating or planning to be pregnant during the trial.
• Clinically significant laboratory abnormalities, which in the opinion of the Investigator may prevent the patient from safely participating in the trial.
• History of solid organ transplantation.
• Any known allergy, hypersensitivity or intolerance to octreotide or any related drug, or other components of CAM2029, or history of any drug hypersensitivity or intolerance that, in the opinion of the Investigator, would compromise the safety of the patient.
• Contraindications to, or interference with, MRI assessments, as dictated by local hospital regulations.
• Previously treated/randomized in the current clinical trial.
• Participation in any other clinical trial to test an investigational drug or device within the last 30 days before screening or during the trial.
• Any other contraindicated serious medical condition that, in the Investigator’s opinion, may prevent the patient from safely participating in the trial.
• Any other current or prior medical condition that may interfere with the conduct of the trial or the evaluation of its results in the opinion of the Investigator.
• Unwilling or unable to comply with the requirements of the protocol or in a situation or condition that, in the opinion of the Investigator, may interfere with participation in the trial.
• On the staff, affiliated with, or a family member of the personnel directly involved with this trial.

Eligibility last updated 9/10/21. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 2/28/23. Questions regarding updates should be directed to the study team contact.

Subjects

• Clinically or genetically confirmed diagnosis of a neurological, psychiatric, or medical condition of interest.
• Age ≥ 18 years at time of diagnosis.

Controls

• Healthy control participants, either a convenience sample of patient’s friends, acquaintances, or family members; or alternatively, community controls, or control outpatients seen at Mayo Clinic.
• Age ≥ 18 years at time of survey.

Subjects

• Age < 18 years at time of diagnosis.
• Inadequate familiarity with the English language.
• Presence of any medical condition or surgical history that could affect the safety of the subject or interfere with study assessments, safety, or the ability of the subject to complete the evaluation per the judgment of the site principal investigator.

Controls

• Age < 18 years at time of survey.
• Inadequate familiarity with the English language.
• Presence of any medical condition or surgical history that could affect the safety of the subject or interfere with study assessments, safety, or the ability of the subject to complete the evaluation per the judgment of the site principal investigator.
• Personal history of the neurological, psychiatric, or medical conditions being studied.

Eligibility last updated 11/17/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Registration:

• Age ≥ 18 years.
  • NOTE: Because no dosing or adverse event data are currently available on the use of PLX038 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Histological confirmed high grade serous ovarian cancer consistent with ovarian, fallopian tube, or primary peritoneal carcinoma (NOTE: Any of these diseases are referred to in this protocol as “ovarian cancer”).
• Recurrent high grade serous ovarian cancer that was initially platinum sensitive (i.e., had at least one platinum-free interval of at least 6 months before progression) is now platinum resistant.
• No more than one prior line of therapy for platinum resistant disease.
  • NOTE: Prior PARP inhibitor therapy is allowed.
• Measurable disease per RECIST 1.1.
• Disease that is amenable to two biopsies.
• Life expectancy greater ≥ 12 weeks.
• ECOG Performance Status (PS) 0, 1 or 2.
• The following laboratory values obtained ≤ 28 days prior to registration:
  • Hemoglobin ≥ 8.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research.

Exclusion Criteria
•Registration:

Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

• Pregnant persons.
• Nursing persons.
• Persons of childbearing potential who are unwilling to employ adequate contraception.
• Histology other than high grade serous carcinoma.
• Prior treatment restrictions.
• Chemotherapy ≤ 4 weeks prior to registration.
• Immunotherapy ≤ 4 weeks prior to registration.
• Radiotherapy ≤ 4 weeks prior to registration.
• Any other investigational therapy ≤ 4 weeks prior to registration.
• History of prior or concurrent malignancy ≤ 2 years prior to registration.
  • Exceptions: If natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.
• Uncontrolled intercurrent illness including, but not limited to:
  • Myocardial infarction within 6 months of study entry;
  • NYHA class III or IV heart failure;
  • Uncontrolled dysrhythmias or poorly controlled angina;
  • History of serious ventricular arrhythmia (VT or VF) and/or factors that predispose to arrhythmia (e.g., heart failure, hypokalemia, family history of Long QT syndrome).
• Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents.
  • Exception: Patients should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better.
• Known HIV.
  • Exception: Patients on effective anti-retroviral therapy with undetectable viral load ≤ 6 months prior to registration are eligible for this trial.
• Known hepatitis.
  • Exception: For patients with evidence of chronic hepatitis B virus infection the HepB viral load must be undetectable on suppressive therapy, if indicated, to be eligible.
  • Exception: Patients with a history of hepatitis C virus infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• Receiving any other investigational agent.
• History of clinically significant gastrointestinal bleeding, colitis, or gastrointestinal perforation.
• 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.
• Requirement for anticoagulation treatment that increases INR or APTT above the normal range.
  • Exceptions: low dose DVT or line prophylaxis allowed.
• Known CNS disease.
  • Exception: Patients with treated brain metastases are eligible if follow-up brain imaging after CNS directed therapy shows no evidence of progression.
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determined that immediate CNS specific treatment is not required and is unlikely to be required during the 1st cycle of therapy.
• Known Gilbert's syndrome or homozygous for the UGT1A1*28 variant allele or other relevant alleles with severely reduced UGT1A1 activity.
• Patients who require treatment with UGT1A1 inhibitors during the planned period of investigational treatment with PLX038.

• Male or female.
• Aged 60 to 90 years, inclusive at Visit 1 Screen.
• Clinical diagnosis of normal cognition, subjective cognitive decline, mild cognitive impairment or mild dementia ( CDR® ≤ 1.5).
• Fluent in English or Spanish.

• Contraindications to MRI such as inability to fit inside the MRI scanner, difficulty with close or confined spaces or presence of MRI non-compatible implants such as pacemakers or aneurysm clips.
• History of or current neurologic, psychiatric or medical disease that could confound the results of the study tests and procedures.
• Clinical diagnosis of moderate or severe cognitive impairment or dementia, requiring assistance with basic activities of daily living.

Eligibility last updated 2/17/22.  Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Patients:

• Patient age 18 or above.
• Confirmed diagnosis of fibromyalgia (FM).
• Patient must be able to understand and provide informed consent and HIPAA authorization.
• Able to speak and read English.

Exclusion Criteria
•Patients:

• Patients < 18 years of age.
• Inability to provide informed consent or HIPAA authorization.
• Individuals that decline study participation.
• Patients without a confirmed diagnosis of FM.

Inclusion Criteria
•Clinicians:

• Clinicians providing care to eligible patients at the Fibromyalgia Clinic and division of General Internal Medicine (Mayo Clinic Jacksonville and Rochester).

Exclusion Criteria
•Clinicians:

• Individuals that decline study participation.

Eligibility last updated 10/1/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Subjects must have undergone bronchoscopic lung volume reduction with endobronchial valve(s) placement for treatment of emphysema at Mayo Clinic-Rochester within timeframe of 3/01/2022 to 2/28/2023.
• Subjects must consent to undergoing CT scan of the chest prior to hospital discharge.

• Previous endobronchial valve placement (i.e., undergoing secondary procedure to have additional valves placed or valves upsized).
• Presence of large post-procedure pneumothorax, as defined by > 2 cm of air present between lung margin and chest wall measured at level of the hilum, identified prior to study CT acquisition.

Eligibility last updated 3/1/22. Questions regarding updates should be directed to the study team contact.

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

Inclusion Criteria;

• Individuals ≥ 18 years old.
• Documentation by a doctor of allergic reactions upon cannabis exposure.

• Individuals < 18 years old.
• Currently undergoing anti-IgE drug treatment (e.g., Omalizumab).

Eligibility last updated 12/3/21. Questions regarding updates should be directed to the study team contact.

Each patient must meet the following criteria to be enrolled in PK Run-in Cohort or the Treatment Cohort of this study:

• Female sex assigned at birth.
• ≥ 18 years of age.
• Not lactating, pregnant, or planning to become pregnant in the next year and agrees to take adequate steps to prevent becoming pregnant 7 days before beginning treatment, during treatment and for 9 months after last dose and not breast feeding during treatment and for 3 months after last dose.
• Must agree to one non-hormonal highly effective method of contraception for the entire duration of study participation. Highly effective methods of birth control are defined as those, alone or in combination, that resulted in a low failure rate of < 1% per year when used consistently and correctly such as intrauterine devices (IUDs, non-hormonal such as copper IUD), sexual abstinence or vasectomized partner. Barrier contraceptives (e.g., male condom or diaphragm) are acceptable if used in combination with spermicides (e.g., foam, gel).
• Premenopausal defined as any female who has experienced menarche and does not meet any of the following criteria for postmenopausal:
  • Permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy); or
  • Amenorrheic for 12 or more months; or
  • Amenorrheic for < 12 or more months and follicle-stimulating hormone (FSH) or plasma estradiol are in the postmenopausal range.
• Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined as estrogen receptor [ER] ≥ 67% or Allred Score 6-8) by local institution protocol.
• Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2.
• Nottingham Grade 1 or 2.
• HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines defined as one of the following:
  • 0 or 1+ by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) not done;
  • 0 or 1+ by IHC and not amplified by FISH;
  • 2+ by immunohistochemistry with average of < 4.0 HER2 signals per cell and an HER2/CEP17 ratio ≥ 2.0;
  • 2+ by immunohistochemistry with average of ≥ 4.0 and < 6.0 HER2 signals per cell and an HER2/CEP17 ratio < 2.0;
  • IHC not done and not amplified by fluorescence in situ hybridization (FISH).
• Clinical Stage IIA or IIB invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging) see Appendix 10.
• Largest tumor diameter2.0 cm either by imaging or clinical examination.
• Magnetic resonance imaging (MRI) ≤ 30 days of registration.
• Mammogram performed ≤ 90 days of registration (Treatment Cohort only).
• Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
• Willing to provide tissue samples for research purposes.

Subjects who meet any of the following criteria will be excluded from the PK Run-in Cohort and the Treatment Cohort:

• Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion.
• Any prior diagnosis or treatment for breast cancer, including carcinoma in situ, or history of any other active malignancy within the past 2 years prior to study entry, with the exception of:
  • Adequately treated in situ carcinoma of the cervix uteri;
  • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin;
  • Any other malignancy with a life expectancy of more than 2 years.
• Any uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection requiring systemic treatment with strong inhibitors/inducers of CYP450 enzymes (including bacterial infection, fungal infection, or detectable viral infection).;
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Uncontrolled symptomatic cardiac arrhythmias;
  • Uncontrolled hypertension (defined as blood pressure > 160/90 mm Hg);
  • Uncontrolled diabetes (Hemoglobin A1c [HbA1c] > 50 mmol/mol);
  • Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 470 milliseconds [msec]) using Fridericia’s QT correction formula seen ≤ 28 days of registration.
• Any of the following co-morbid conditions:
  • Known cataracts or retinopathy;
  • History of deep vein thrombosis (DVT)/pulmonary embolism (PE);
  • Known activated protein C (APC) resistance, an inherited coagulation disorder.
• Evidence of the following laboratory abnormalities ≤ 28 days prior to registration:
  • Creatine clearance < 60 ml/hr by the Cockcroft-Gault equation;
  • Total bilirubin ≥ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) or alanine amino transferase (ALT) ≥ 2.5 x ULN;
  • Platelet count (PLT) ≤ 75,000/mm^3 ;
  • Hemoglobin (Hb) ≤ 10 g/dL.
• Hormonal therapies including birth control and hormone replacement therapy during the study or within 1 week of registration.
• Allergy to endoxifen, goserelin, or exemestane or any of their components.
• Participation in another investigational clinical trial ≤ 6 months of registration.
• Not willing or able to understand the study information and/or informed consent.

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

Eligibility last updated 11/7/22. Questions regarding updates should be directed to the study team contact.

• Men and women, ≥ 18 years of age.
• The patients is eligible to undergo WATCHMAN device implant procedure.
• The patient is eligible for short term anticoagulation therapy.
• Ability to tolerate the procedure without the need for general anesthesia as assessed by the treating physician(s).
• Ability to give informed consent for the procedure.
• The patient is able and willing to undergo the procedure under moderate sedation.
• The patient is able and willing to return for required 45-day TEE.

• Patient has contraindication for short term anticoagulation.
• The patient has history of a hypercoagulable state per medical record documentation.
• Pregnancy or planning to get pregnant during the investigation.

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

• Patient must be ≥ 18 years of age.
• Patient must have histologically confirmed adenocarcinoma of the rectum with the inferior margin within 15 cm from the anal verge based on colonoscopy and/or flexible sigmoidoscopy.
• Patient must have T3-4Nx or TxN+ disease (stage II or III) based on magnetic resonance imaging of the pelvis and computed tomography of the chest and abdomen. These baseline scans must be done within 28 days prior to registration.
• Patient must have MSI-H (microsatellite instability-high) or dMMR (deficient mismatch repair) tumors based on immunohistochemistry or PCR (polymerase chain reaction).
• Patient must have Eastern Cooperative Oncology Group (ECOG) Performance status 0-2.
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.
• Patient must agree to not receive live vaccines while on this study.
• Patients of childbearing potential and sexually active patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for at least one month (female patients) or one week (male patients) prior to the start of study drug and continue for 5 months after the last dose of study drug (for female patients). Investigators must counsel patients on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
• Leukocytes ≥ 3,000/mcL (must be obtained ≤ 14 days prior to protocol registration).
• Absolute neutrophil count (ANC) ≥ 1,500/mcL (must be obtained ≤ 14 days prior to protocol registration).
• Platelets ≥ 100,000/mcL (must be obtained ≤ 14 days prior to protocol registration).
• Total bilirubin ≤ institutional upper limit of normal (ULN) (must be obtained ≤ 14 days prior to protocol registration).
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x institutional ULN (must be obtained ≤ 14 days prior to protocol registration)
• Creatinine ≤ 1.5 x institutional ULN (must be obtained ≤ 14 days prior to protocol registration).
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

• Patient must not have previously received chemotherapy or immunotherapy for rectal cancer.
• Patient must not have previously received radiotherapy to the pelvis.
• Patient must not have had major surgery performed within 28 days prior to registration.
• Patient must not have a history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest computed tomography (CT) scan.
• Patient must not have a serious active infection requiring IV antibiotics at time of registration.
• Patient must not have active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater). These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patients with any of these are ineligible for this study because of the risk of recurrence or exacerbation of disease.
• Patient must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to registration. Inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A repeat pregnancy test must be done within 72 hours prior to first dose of treatment if the baseline test was done outside the 72 hour window. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Eligibility last updated 9/14/21. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/21/22. Questions regarding updates should be directed to the study team contact.

• Patient is male or female and is 2 months to 24 months of age, inclusive.
• Patient has been diagnosed with IS within 6 weeks prior to Screening. Diagnostic criteria include both clinical spasms and an electroencephalogram (EEG) pattern consistent with hypsarrhythmia or significant abnormality compatible with IS.
  • NOTE: If a video EEG is performed at the clinical site within 48 hours prior to the patient's parent/guardian providing written informed consent, and it meets the criteria, this video EEG may be used as the screening/baseline EEG for the study.
• Patient has normal renal function as defined by an estimated glomerular filtration rate (eGFR).
• > 60 mL/min/1.73 m^2, calculated as eGFR = 0.413 x (height [cm]/ serum creatinine [mg/dL]).
• Patient's legally authodzed representative (i.e., parent or guardian) must provide written informed consent obtained per Institutional Review Board policy and requirements, consistent with the International Council for Harmonisation.
• Patient's parent/guardian is able to understand and willing to comply with study procedures and restrictions.

• Patient has been diagnosed with tuberous sclerosis.
• Patient has acute illness considered clinically significant by the Investigator within 30 days prior to Screening.
• Patient has a diagnosis of recent systemic fungal infection; history of ocular herpes simplex; history of or current peptic ulcer; uncontrolled hypertension or congestive heart failure; or any other condition that would be significantly impacted by the study drug.
• Patient has a preplanned surgery or procedurc(s) that would interfere with the conduct of the study.
• Patient has received any prior treatment for IS.
• Patient has been previously treated with adrenocorticotropic honnonc (ACTH), corticosteroids, or vigabatrin for seizures.
• Patient has been previously treated with a course of corticosteroids for an indication other than seizures within 30 days prior to Screening.
• Patient has a known or suspected allergy to ACTH or vigabatrin or any component of AMZ002 or vigabatrin.
• Patient has used any other investigational drug within 30 days or 5 half-lives prior to the first dose of AMZ002 or vigabatrin (whichever is longer).
• Patient's parent/guardian is unable to provide written informed consent and/or to complete the daily diary.
• Patient has any other disease, condition, or therapy that, in the opinion of the Investigator, might compromise safety or compliance, preclude the patient from successfully completing the study, or interfere with the interpretation of the results.

Eligibility last updated 9/15/21. Questions regarding updates should be directed to the study team contact.

• Participant must be able to understand and provide informed consent and be willing to comply with study procedures and follow up.
• Are at least 18 years of age and not older than 70 years of age at screening.
• Meet the ACR/EULAR Classification Criteria for IgG4-RD.
• Have active disease based at screening on an IgG4-RD RI ≥ 4, with disease manifestations in at least two organ systems.
• May have newly-diagnosed or relapsing disease at screening. Relapsing disease is defined as IgG4-RD that has previously been in remission but is now active again.
• May be on treatment or off treatment at the time of screening. If on treatment, must be willing to discontinue those other treatments before the baseline visit.
• No history of severe allergic reactions to monoclonal antibodies.
• Female participants of childbearing potential must have a negative pregnancy test upon study entry.
• Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to consistently and correctly use FDA approved highly effective methods of birth control, for the entire duration of the study.
• Immunization with one of the FDA authorized or licensed SARS-CoV2 vaccines is required for study entry. Vaccination series must have been completed at least 2 weeks prior to start of study therapy.
• Participants with COVID-19 infections within the preceding three months must have 2 consecutive negative nasal swab PCR tests performed at least 24 hours apart.

• Presence of a condition other than IgG4-RD that (e.g., asthma) is likely to require systemic Glucocorticoids (GC) for disease control during the period of the trial.
• Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin.)
• the following lab values as indicators of hepatic dysfunction:
  • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times the upper limit of normal (ULN);
  • Total bilirubin > two times the ULN unless caused by Gilbert’s disease. Gilbert’s disease with total bilirubin > three times ULN;
  • Serum albumin < 2.5 mg/dL.
• Evidence of another uncontrolled condition which, in the judgment of the investigator, could interfere with participation in the trial according to the protocol.
• Active infection requiring hospitalization or treatment with systemic antimicrobial agents within the 30 days prior to randomization.
• Prior use of rituximab or other B cell depleting agents within 9 months of enrollment unless B cells have been demonstrated to have repopulated.
• Use of any investigational agent or biologic and non-biologic DMARDSwithin 5 half-lives of the agent (or 6 months if the half-life is unknown) prior to enrollment.
• Any of the following laboratory tests at the Screening Visit:
  • White blood cell (WBC) count < 3.0 x 10^3/µL;
  • Absolute neutrophil count (ANC) < 1.5 x 10^3/µL;
  • Hemoglobin < 10 g/dL;
  • Platelet count < 75 x 10^9/L;
  • Estimated glomerular filtration rate (eGFR) ≤ 45 ml/minute/1.73m^2.
• The use of supplemental oxygen at baseline.
• Positive Quantiferon gold assay. Indeterminate Quantiferon gold assays must be repeated(with same or other interferon gamma release assay (IGRA) per local policy) and shown to be negative. Alternatively, if the Quantiferon gold assay remains indeterminant, a participant must have a negative PPD. Finally, if the participant has had the Bacille Calmette-Guerin (BCG) vaccine or has some other condition complicating the interpretation of TB testing, consultation with infectious disease specialist must be obtained before receipt of the first investigational infusion.
  • Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 days before their first investigational infusion.
• Medical history or serologic evidence at Screening of chronic infections including:
  • Human immunodeficiency virus infection;
  • Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity;
  • Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody positive, they will be eligible to participate in the study if he/she is negative for viral load at Screening.
• Live vaccines within 8 weeks of initiating study therapy.
• Participantis pregnant or breastfeeding, or planning a pregnancy while enrolled in the study.
• Substance use disorder, including the recurrent use of alcohol and/or drugs within the past year associated with clinically significant impairment associated with failure to meet major responsibilities at work, school, or home.
• IgG4-RD that is dominated primarily by advanced fibrotic lesions. Specifically, participants whose disease manifestations consist only of:
  • retroperitoneal fibrosis;
  • fibrosing mediatinitis;
  • sclerosing mesenteritis; and
  • Riedel’s thyroiditis. Participants with these disease manifestations can be included; however, only if they have disease in 2 organ systems that is not of an advanced fibrotic nature and otherwise meet the Inclusion and Exclusion Criteria.

Eligibility last updated 8/11/22. Questions regarding updates should be directed to the study team contact.

• Age 18 or older.
• Diagnosis of keratoconus.
• Available baseline corneal topography and pachymetry.
• Amsler-Krumeich keratoconus classification of stage 1 or higher.

• No prior corneal transplantation or INTACTS.
• No prior use of hybrid, corneal or scleral gas permeable lenses.
• Presence of corneal scarring.

Eligibility last updated 9/17/21. Questions regarding updates should be directed to the study team contact.

• Both males and females will be enrolled and must be at least 18 years of age.
• Patients with a known history of IBD and dysplasia (low grade or high grade) undergoing surveillance.
• Only patients who undergo both WATS and standard biopsy will be included in this study.
• Institutional Review Board (IRB)-approved consent must be signed by patients to participate in this study.

• Individuals < 18 years of age.

Eligibility last updated 2/7/22. Questions regarding updates should be directed to the study team contact.

For patients still alive:

• Enrolled in BEAUTY Study (MC1137) and did not withdraw consent while enrolled on BEAUTY for either specimen collection or long-term follow-up.
• Able to provide written informed consent.
• Willingness to provide mandatory blood specimens for future research on breast cancer at Mayo Clinic.
• Willingness to provide mandatory tissue specimens for future research on breast cancer at Mayo Clinic.
• Willingness to provide consent for use of archived tumor biopsies obtained after enrollment in BEAUTY (Request tissue from prior biopsy of site of recurrence).
• Ability to complete questionnaires by themselves or with assistance.

For patients who have died:

• Enrolled in MC1137 and did not withdraw consent while enrolled on BEAUTY for either specimen collection or long-term follow-up.
• Existence of a family member willing to provide consent for use of archived tumor biopsies obtained after enrollment in BEAUTY.

• Not enrolled in BEAUTY study (MC1137).

Eligibility last updated 6/30/22. Questions regarding updates should be directed to the study team contact.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection).
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm);
  • By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible);
  • Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen;
    • ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.
  • The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive;
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

• Definitive clinical or radiologic evidence of metastatic disease. -pT2
  •pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible).
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible).
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible).
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible.
• Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.
• 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 study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Eligibility last updated 9/20/21. Questions regarding updates should be directed to the study team contact.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection).
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm);
  • By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible);
  • Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen;
    • ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.
  • The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive;
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

• Definitive clinical or radiologic evidence of metastatic disease. -pT2
  •pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible).
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible).
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible).
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible.
• Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.
• 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 study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Eligibility last updated 9/20/21. Questions regarding updates should be directed to the study team contact.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection).
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm);
  • By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible);
  • Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen;
    • ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.
  • The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive;
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

• Definitive clinical or radiologic evidence of metastatic disease. -pT2
  •pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible).
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible).
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible).
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible.
• Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.
• 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 study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Eligibility last updated 9/20/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Patient has undergone office-based evaluation for hematuria (CT, ultrasound, cystoscopy).

• Patient has known cancer outside of the target cancer 5 years prior to current collection (not including basal cell or squamous cell skin cancers; if patient has not been seen or if information is not available, the patient is eligible).
• Patient has recurrent bladder cancer.
• Patient has ever been previously diagnosed with UTUC (Upper Tract Urothelial Carcinoma) prior to bladder resection.
• Patient has prior diagnosis of bladder cancer for which intravesical immunotherapy (BCG) or chemotherapy (Mitomycin, Valrubicin) was provided.
• Patient has received chemotherapy class drugs for the treatment of cancer in the 5 years prior to current collection.
• Patient has had any prior radiation therapy to the target lesion prior to current collection.
• Patient has had a biopsy to the target organ and/or lesion within 3 days before collection.
• Patient has undergone cystectomy.
• Patient has transurethral instrumentation (placement of urinary catheter) within 7 days prior to urine collection.
• Patient has had a urinary tract infection within 14 days prior to urine collection.
• Patient has chronic indwelling urinary catheter 
• Patient has prior diagnosis of bladder cancer for which prior resection of tumor was performed.

Eligibility last updated 6/29/22. Questions regarding updates should be directed to the study team contact.

• Adults, age ≥ 18 years.
• Any concomitant malignancy being treated with any PD-1 inhibitor (pembrolizumab, nivolumab or cemiplimab) as monotherapy and the presence of inflammatory arthritis defined by:
  • provider documented inflammatory arthritis (meet 2010 EULAR/ACR classification criteria of RA) in one or more large or small joints; and at least one or more of the following:
  • elevated inflammatory markers;
  • supportive imaging and/or supportive synovial fluid analysis.

• Active infection.
• Prior history of the rheumatic disease.
• Any B cell depletion therapy.
• PActive use of high (≥ 30 mg daily) of prednisone or steroid equivalent.
• Clinical features suggestive of non-RA autoimmune rheumatic disease (e.g., lupus, Sjogren’s, psoriatic arthritis, etc.) or axial spondyloarthropathy.

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

• Prior TNFi biologic treatment – Patient has active, moderate-high disease activity RA (CDAI ≥ 10 and HAQ ≥ 0.5) despite the use/experience for ≥ 3 months of a TNFi-biologic OR discontinued the medication(s) due to intolerability or toxicity irrespective of treatment duration prior to the first dose of study drug; AND
• Glucocorticoid and NSAID treatment
  •If receiving glucocorticoids (≤ 10 mg/day of prednisone of equivalent) or NSAIDs, on stable doses for ≥ 2 weeks prior to randomization; AND
• Insurance
  •Insurance plan or patient assistance program allows access to at least 1 drug in each of the two treatment strategies for 1 year trial duration. Participants will be allowed to continue their conventional synthetic DMARD (csDMARD) therapy if they had been using it for ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of study drug. The following csDMARDs are allowed: methotrexate (MTX), sulfasalazine, hydroxychloroquine, and leflunomide (TNFi-biologic and tsDMARD) through insurance plan or a patient assistance program/plan.

• Prior treatment with more than three biologics, defined as TNFi-biologic or non-TNFi biologic.
• Prior treatment with targeted synthetic DMARD.
• Concomitant use of cyclosporine, or azathioprine within 2-months before randomization.
• History of sensitivity to all 4 non-TNF-biologic or a targeted synthetic DMARD.
• Glucocorticoid injection (intravenous, intramuscular, or intraarticular) within 1 month of study entry.
• Live vaccine within 90 days of study entry.
• Acute infection treated with parenteral antibiotics or hospitalization within 1 month or with oral antibiotics within 2 weeks of study entry; or chronic infections requiring long-term antibiotic suppressive therapy.
• History of HIV or opportunistic infections.
• New York Heart Association Class III or IV heart failure.
• Latent TB not treated with anti-mycobacterial medication.
• Untreated Hepatitis B or C infection.
• History of deep venous thrombosis or pulmonary embolism.
• Pregnant or nursing women.
• History of herpes zoster or shingles.

Eligibility last updated 6/1/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 7/26/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 1/13/23. Questions regarding updates should be directed to the study team contact.

• Patient is ≥ 18 years of age.
• Patient or patient’s legal representative is willing and able to provide written informed consent.
• Patient is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
• The patient must have advanced cutaneous melanoma or acral melanoma; no more than 5 patients with acral melanoma may enroll in this cohort (Cohort 1). Or, the patient must have unresectable and/or metastatic mucosal melanoma (Cohort 2).
• Patient must have received previous treatment as follows:
  • patient has received anti-PD-[L]1 therapy ± anti-CTLA-4 therapy, and ≤ 1 other prior regimen of systemic anti-neoplastic therapy;
  • patient should have experienced objective response (PR or CR) or SD as BOR to anti-PD-[L]1 therapy;
  • patients with BRAF mutations may or may not have received prior targeted therapy.
• A patient who has received prior treatment with talimogene laherparepvec (TVEC) is allowed to enroll provided that last exposure to TVEC was ≥ 28 days prior to first exposure to nemvaleukin and that all injection-site reactions to TVEC have resolved. TVEC shall not be considered a prior regimen of systemic anti-neoplastic therapy, nor shall it be considered a systemic immunomodulatory agent.
• Patient has at least one measurable lesion that qualifies as a target lesion based on RECIST 1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are not considered measurable unless there has been demonstrated progression in the lesion.
• Patient is willing to undergo a pretreatment tumor biopsy or provide qualifying archival tumor tissue. To qualify, archival tissue must have been sampled after last exposure to any systemic anti-neoplastic agent (including TVEC). Patients unable to undergo a biopsy may be enrolled if risk/benefit ratio of biopsy is considered unfavorable and/or when a biopsy would likely lead to significant delays in care. This decision must be accompanied by supporting documentation from the Investigator and performed in consultation with Medical Monitor. All pretreatment tissue must have been collected no more than 120 days prior to screening.
• Patient has recovered from the effects of any previous chemotherapy, immunotherapy, other prior systemic anticancer therapy, radiotherapy, and/or surgery (i.e., residual toxicity no worse than Grade 1 [Grade 2 treatment-associated peripheral neuropathy and/or any grade of alopecia are acceptable assuming all other inclusion criteria are met]).
• Patient who has received prior systemic anti-neoplastic agent(s) must wait at least 5 half-lives or 4 weeks (whichever is shorter) following prior therapy before enrollment into the study, or 4 weeks if the half-life of a given investigational agent is not known.
• Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 within 5 days before the first dose of study drug and an estimated life expectancy of at least 3 months.
• Patient has adequate hematologic reserve as evidenced by:
  • Absolute neutrophil count (ANC) of ≥ 1000/µL;
  • Absolute lymphocyte count of ≥ 500/µL;
  • Platelet count of ≥ 75,000/µL; and
  • Hemoglobin of ≥ 9 g/dL (patients may be transfused to this level if necessary, but transfusion must occur > 1 week prior to the first dose of study drug).
• Patient has adequate hepatic function as evidenced by aspartate transaminase and alanine transaminase values ≤ 3 × the upper limit of normal (ULN) and serum total bilirubin values of ≤ 1.5 × ULN (≤ 2 × ULN for patients with known Gilbert’s syndrome) for the reference laboratory measured within 7 days prior to the first dose of study drug. For patients with documented baseline liver metastasis, the following limits will apply: 5 × ULN for transaminase and 2 × ULN for bilirubin.
• Patient has adequate renal function as evidenced by a serum creatinine ≤ 1.5 × the ULN for the reference laboratory or a calculated creatinine clearance of ≥ 45 mL/min by the Cockcroft-Gault Equation measured within 7 days prior to the first dose of study drug.
• Patient has international normalized ratio (INR) AND/OR prothrombin time (PT) AND activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy, in which case INR and/or PT and aPTT must be within the desired therapeutic range of intended use for such anticoagulants.
• Patient agrees to abide by the contraceptive requirements detailed in the protocol.
• Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum or urine) within 3 days before the first dose of study drug (see the protocol for the definition of WOCBP).

• Patient has uveal melanoma.
• Patient has received prior IL-2-based or IL-15-based cytokine therapy; patient has had exposure, including intralesional, to IL-12 or analogs thereof.
• Patient has received radiotherapy within the last 4 weeks before start of study treatment, with the exception of limited field palliative radiotherapy to an area not inclusive of or adjacent to the target lesion(s), that has been completed at least 2 weeks before starting study treatment with no ongoing acute sequelae (eg, radiation burns).
• Patient requires systemic corticosteroids (> 10 mg of prednisone daily, or equivalent) or patient has taken systemic corticosteroids (> 10 mg of prednisone daily, or equivalent) within 14 days prior to the first dose of study drug; however, replacement doses, topical, ophthalmologic, and inhalational steroids are permitted.
• Patient has taken non-steroid systemic immunomodulatory agents (e.g., Enbrel®, Humira®, etc) within 28 days prior to the first dose of study drug or anticipates use of these therapies during the study period.
• Patient has undergone prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow transplant.
• Patient has received a live or live-attenuated vaccine(s) within 30 days prior to the first dose of study treatment.
  • Note: COVID-19 vaccine is allowed.
• Patient has received more than 3 doses of therapeutic systemic broad-spectrum antibiotics within 14 days prior to the first dose of study drug. Antibiotics given for peri-procedural prophylaxis or given presumptively for a limited time (eg, until infection was ruled out), as well as topical or intra-ocular antibiotics, shall not be exclusionary.
• Patient has had any active infection and/or a fever ≥ 38.5°C (≥ 101°F) within 3 days prior to the first dose of study drug.
• Patient has active autoimmune disease(s) requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that has required chronic or frequent systemic steroids. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed.
• Patient has underlying chronic lung disease, chronic obstructive pulmonary disease, metastatic lung disease, pleural effusions or other lung disorders (eg, pulmonary embolism) with a baseline room air oxygen saturation of < 92% at screening, and/or dyspnea (≥ Grade 3), which requires oxygen therapy.
• Patient has any other concurrent uncontrolled illness, including mental illness or substance use, which may interfere with the ability of the patient to cooperate and participate in the study. Other examples of such conditions would include unstable, poorly controlled, or severe hypertension; clinically significant pericardial effusion; New York Heart Association Class III or Class IV congestive heart failure; high risk cardiovascular disease, defined as unstable angina, myocardial infarction, or cerebrovascular accident within 6 months of first dose; uncontrolled diabetes mellitus that has required 2 or more hospitalizations in the last year and/or emergent management within the last 6 months; severe peripheral vascular disease; or recent serious trauma.
• Patient has had an active second malignancy within the previous 2 years. This criterion does not apply to patients with adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, prostate cancer of highest Gleason score ≤ 6 with undetectable prostate-specific antigen over the previous 12 months, urothelial carcinoma in situ, or ductal carcinoma in situ of the breast that has undergone full surgical resection.
• Patient is currently pregnant, breastfeeding, or is planning to become pregnant or to begin breastfeeding during the study period or within 30 days after last study drug administration.
• Patient has active or symptomatic central nervous system metastases unless all the following have been met: such metastases have been treated by surgery and/or radiation therapy, and/or gamma knife and have remained radiographically stable (or shrinking) on 2 consecutive imaging examinations performed at least 6 weeks apart; AND steroids have been tapered to a dose of 10 mg of prednisone (or equivalent) or less for at least 2 weeks prior to first dose of study agent(s); AND the patient is neurologically stable. Patients with history of brain metastases or a suspicion of brain metastases must have a brain magnetic resonance imaging (MRI) at baseline (Screening Visit).
• Patient has known or suspected hypersensitivity to any components of nemvaleukin.
• Patient has active uncontrolled coagulopathy.
• Patient has QT interval corrected by the Fridericia Correction Formula values of > 470 msec (in females) or > 450 msec (in males); patient who is known to have congenital prolonged QT syndromes; or patient who is on medications known to cause prolonged QT interval on ECG.
• Patient is known to be positive for human immunodeficiency virus. Patients with known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) are excluded; however, a patient with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) may be enrolled provided that HBV DNA is negative. Patients with known active hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] are detected) are excluded, however, a patient with cured hepatitis C (negative HCV RNA status) may be enrolled.
• Patient has active or latent tuberculosis. Patients with cured tuberculosis may be enrolled.
• Patient has developed Grade ≥ 3 immune-related adverse events (irAEs) while on prior immunotherapy (e.g., pneumonitis, nephritis, and neuropathy). Patients who have immunerelated endocrinopathies and are stable on hormone replacement therapy are not excluded. Patients who experienced colitis as a toxicity of prior immunotherapy must have undergone colonoscopy since last symptoms of colitis that confirms the absence of ongoing inflammation. Vitiligo is not exclusionary.

Eligibility last updated 9/24/21. Questions regarding updates should be directed to the study team contact.