• 18-65 years of age
• Individuals who have undergone surgical reconstruction of the brachial plexus.
• Subjects who are in good neuromuscular health with no previous musculoskeletal disease.
• Patients with injuries resulting in loss of elbow flexion, in particular a traumatic brachial plexus injury
• Functional passive range of motion of the involved upper extremity
• Able to follow simple directions
• Willingness to participate in the study
• No restriction will be placed on gender, race, or ethnicity.

• Closed head injury with resultant inability to follow commands.
• Soft tissue or skeletal injuries which preclude use of an orthosis.
• Non-functional passive range of motion.
• Neuropathic pain which prevents use of a powered exoskeleton.

Eligibility last updated 12/15/21. Questions regarding updates should be directed to the study team contact.

• Male or female age 18-75 years.
• Have successfully completed a full course of a standard of care CDI antibiotic for a qualifying CDI episode (primary or recurrent) within 3 to 7 days of randomization:
  • Qualifying episode of CDI meets the following definition:
    • Positive stool C. difficile toxin (NAAT, EIA, CCTA, or equivalent test) as documented by study site; AND
    • History of ≥ 3 unformed (Bristol scores of 5, 6, or 7) bowel movements per day for at least 24 hours; AND
    • Received standard of care antibiotic treatment for CDI diagnosis.
• Prior to the first dose of study drug, completion of standard of care antibiotic therapy with oral vancomycin, metronidazole, or fidaxomicin for CDI with a treatment duration of 10 to 21 days.
• Clinical cure assessed and confirmed at screening and reconfirmed at Day 1 visit (randomization). Clinical cure must meet the following definition:
  • ≤ 2 unformed stools per day for at least 2 consecutive days and maintained through Day 1 without the need for further antibiotic therapy.
• Subject is able to begin treatment with study drug within 3 to 7 days following completion (i.e., last dose) of the CDI antibiotic course for the qualifying CDI episode.
• For female subjects of childbearing potential, be using an insertable, injectable, transdermal, or combination oral contraceptive approved and deemed highly effective by the United States Food and Drug Administration through 30 days after the last dose of study drug and have negative results on a serum pregnancy test at the Screening visit and a urine pregnancy test on Day 1.
  • NOTE: women who are surgically sterile or postmenopausal (i.e., no menses for at least 2 years or documented by follicle stimulating hormone) are also eligible to participate.
• For male subjects, vasectomized more than 6 months prior to study drug administration, or if non-vasectomized are required to practice reliable birth control methods (condom) or female partner of childbearing potential must use an effective birth control method through 30 days after the last dose of study drug.
• Understand the risks and benefits of participation and are able and willing to provide written informed consent.
• Willing and able to meet all study requirements including collection, handling, storage, and transport of stool samples to clinical site and attending all assessment visits and phone calls.

• Body mass index ≥ 40.0 kg/m^2.
• Life expectancy of ≤ 12 months.
• Inpatient (in hospital or skilled nursing facility) at the time of randomization.
• Current (i.e., qualifying) CDI episode required admission to an Intensive Care Unit.
• Pregnant, breastfeeding, or seeking pregnancy while on study.
• Have, as determined by the Investigator, a history or clinical/laboratory manifestations of significant neurological, renal, hepatic, hematologic, cardiac, pulmonary, metabolic, endocrine, psychiatric, gastrointestinal disorders other than CDI (including infectious, ischemic, or immunological diseases), HIV, HBV, and/or HCV infection, or other condition that could interfere with the evaluation of safety or efficacy, or put the subject at risk of harm from study participation.
• Have an active malignancy of any type or history of a malignancy within past 5 years, except for treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
• Have an acute febrile illness (fever > 38°C [100.4°F]) at Day 1.
• Drug, alcohol, or substance dependence within the last 2 years.
• Anticipated hospital admission for any reason while on study.
• Any of the following laboratory results at Screening:
  • White blood cell count ≥ 15,000 cells/mm^3;
  • Absolute neutrophil count 1.8 mg/dL.
• Use of systemic antibiotic therapy for conditions other than CDI within 7 days of randomization or expectation to require antibiotic therapy for conditions other than CDI for 12 weeks following the first dose of study drug for Cohort A or 16 weeks following the first dose of study drug for Cohort B, including subtherapeutic doses of oral antibiotics (e.g., for rosacea).
• Have a known immunodeficiency disorder, including but not limited to:
  • An immunodeficiency disease;
  • Receiving, or plans to receive, treatment with systemic corticosteroids equivalent to > 10 mg prednisone per day;
  • Receiving, or plans to receive, myelosuppressive chemotherapy.
• Previous fecal transplant or live biotherapeutic product within 1 year of randomization.
• Treatment with bezlotoxumab (Zinplava™) for the qualifying CDI episode.
• Diagnosis of inflammatory bowel disease (including but not limited to: Crohn’s disease, ulcerative colitis, microscopic colitis), active irritable bowel syndrome [those with diarrhea predominant or alternating constipation and diarrhea] (in past 2 years based on Rome IV criteria and subject deemed not suitable for study by Investigator’s judgment), celiac disease not well controlled on gluten-free diet, active gastroparesis, toxic megacolon, pseudomembranous colitis, colostomy, intestinal resection (except appendectomy), ileus or short gut syndrome.
• History of chronic diarrhea.
• Intra-abdominal surgery, including laparoscopic procedures, within 8 weeks of Screening (appendectomy and cholecystectomy excluded).
• History of difficulty swallowing food or liquids.
• Taking antidiarrheal agents (e.g., loperamide) on a regular basis.
• Use of non-dietary probiotic supplements within 7 days of Day 1 or plan to use non-dietary probiotic supplements while on study through Week 12 in Cohort A and Week 16 in Cohort B.
• Known to have consumed fermented or other foods that may contain B. amyloliquefaciens (such as miso, soybean paste, or fermented rice- or locust bean-derived products) within 7 days prior to Day 1, or plan to consume them prior to Week 12 for Cohort A and prior to Week 16 for Cohort B.
• In the opinion of the Investigator, unable to comply with the study protocol.
• Participation in a clinical trial of an investigational drug or medical device within 30 days prior to the Screening visit.

Eligibility last updated 8/30/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Cohort A: Patient must have smoldering multiple myeloma requiring treatment and no prior therapies.
• Cohort B: Patient must have newly diagnosed myeloma requiring treatment and no prior therapies.
• Cohort C: Patient must have relapsed or refractory multiple myeloma with at least one prior therapy for their multiple myeloma but not refractory to all IMiDs.
• Cohort D: Patient must have relapsed or refractory multiple myeloma with Lenalidomide as part of a maintenance regimen as their most recent therapy.
• Measurable disease.
• Provide written informed consent.
• Patient must be considered for treatment with an IMiD containing regimen.
• ECOG Performance Status (PS) 0, 1, 2 or 3.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Hemoglobin ≥ 7.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1000/mm^3;
  • Platelet count ≥ 50,000/mm^3;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) unless due to Gilbert’s syndrome, in which case the direct bilirubin must be ≤ 1.5 X ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • PT/INR/aPTT ≤ 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy;
  • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula below:
• Cockcroft-Gault Equation:
• Creatinine clearance for males =
• (140
  •age)(weight in kg) ( 72)(serum creatinine in mg/dL);
• Creatinine clearance for females = (140
  •age)(weight in kg)(0.85) ( 72)(serum creatinine in  mg/dL).
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
  • NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.  
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood and bone marrow specimens for correlative research.
• Willing to follow the requirements of the Pomalyst® REMS program.

• 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.
• 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.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History of myocardial infarction ≤ 6 months.

Eligibility last updated 11/28/22. Questions regarding updates should be directed to the study team contact.

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.

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

Eligibility last updated 5/16/23. Questions regarding updates should be directed to the study team contact.

• Patients undergoing a MR brain without and with contrast examination on any GE or Siemens 1.5T and 3T MRI system within Mayo Clinic, Rochester, as part of their care plan.

• None.

Eligibility last updated 9/30/21. Questions regarding updates should be directed to the study team contact.

• Pregnant patients seen for prenatal care in Rochester and deliver within the Mayo Clinic Health Systems
• Ability to provide informed written consent
• Known paternity for pregnancy
• Singleton pregnancies

• Mothers < 18 years of age
• Multiple fetuses

Eligibility last updated 9/8/22. Questions regarding updates should be directed to the study team contact.

• Signed Informed Consent Form.
• Age 18 to 75 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Diagnosis of pMN according to renal biopsy prior to or during screening.
  • Diagnosis should be based on light and immunofluorescence microscopy, and if possible, electron microscopy.
• UPCR ≥ 5 g from 24-hour urine collection despite best supportive care for ≥ 3 months prior to screening or UPCR ≥ 4 g despite best supportive care ≥ 6 months prior to screening.
  • Best supportive care comprises renin-angiotensin system blockade with ACE inhibitor and/or ARB at maximally tolerated approved dose.
• Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at screening
• eGFR ≥ 40 mL/min/1.73m^2 or qualified endogenous creatinine clearance ≥ 40 mL/min based on 24-hour urine collection during screening. eGFR is calculated using the CKD-EPI equation (Levey, et al. 2009).
• Patients who previously responded to CNIs (CsA or tacrolimus), rituximab, or alkylating agents with either a CR or PR and subsequently relapsed are eligible but require discontinuation of CNIs or alkylating agents for ≥ 6 months and rituximab for ≥ 9 months prior to screening.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraception during the treatment period and for 18 months after the final dose of obinutuzumab and for 28 days after the final dose of tacrolimus.
  • 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.
  • The following are examples of adequate contraceptive methods: bilateral tubal ligation; male sterilization; hormonal contraceptives; hormone-releasing intrauterine devices; copper intrauterine devices; male or female condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.
  • 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 receiving tacrolimus:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, as defined below:
  • 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 preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
  • With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 28 days after the final dose of tacrolimus to avoid exposing the embryo.
  • For patients enrolled in the extended China enrollment phase at NMPA-recognized sites: current resident of mainland China and of Chinese ancestry.

• Patients with a secondary cause of MN (e.g., hepatitis B, SLE, medications, malignancies).
• Uncontrolled blood pressure, in the opinion of the investigator, during 3 months prior to screening.
• Evidence of ≥  50% reduction in proteinuria during the previous 6 months prior to randomization.
• Receipt of renal replacement therapy (e.g., renal transplantation, chronic dialysis).
• Type 1 or 2 diabetes mellitus (to exclude proteinuria secondary to diabetic nephropathy).
• Patients who have recent history of steroid-induced diabetes but no evidence on renal biopsy for diabetic nephropathy performed within 6 months of entry into the study are eligible.
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 18 months after the final dose of obinutuzumab or 28 days after the final dose of tacrolimus.
• Women of childbearing potential, including those who have had a tubal ligation, must have a negative pregnancy test result within 1 day prior to each obinutuzumab infusion.
• History of resistance (no response) to CNIs or B-cell depleting antibodies.
• Patients with non-response to rituximab due to development of human anti-chimeric antibodies will be eligible.
• Receipt of previous therapies as follows:
  • Treatment with MMF or oral, intramuscular, or intravenous corticosteroids within 1 month prior to screening;
  • Any B-cell depleting therapy such as rituximab, ocrelizumab, or ofatumumab within 9 months prior to screening;
  • Treatment with cyclophosphamide or CNI within 6 months prior to screening;
  • Treatment with any biologic therapy (other than B-cell depleting agents) such as belimumab, ustekinumab, or anifrolumab (investigational) within 6 months prior to screening;
  • Treatment with an inhibitor of Janus-associated kinase, Bruton’s tyrosine kinase, or tyrosine kinase 2, including but not limited to tofacitinib, baricitinib, upadacitinib, filgotinib (investigational), ibrutinib, or fenebrutinib (investigational) within 3 months prior to screening;
  • Treatment with any investigational agent within 28 days of screening or 5 drug-elimination half-lives of the investigational drug, whichever is longer;
  • Receipt of a live vaccine within 28 days prior to screening or during screening.
• Thrombocytopenia, anemia, and/or coagulopathy with high risk for clinically significant bleeding or organ dysfunction or requiring plasmapheresis, IVIg, or acute blood product transfusions.
• Significant or uncontrolled medical disease which, in the investigator’s opinion, would preclude patient participation.
• Known HIV infection. 
• 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.
• Known active infection of any kind, excluding fungal infection of the nail beds.
• Any major episode of infection requiring hospitalization or treatment either with IV anti-infective treatments during the 2 months prior to or during screening or with oral anti-infective treatments during the 2 weeks prior to or during screening.
• 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, except non-melanomatous carcinomas of the skin that have been treated or excised and have resolved.
• Major surgery requiring hospitalization within the 4 weeks prior to screening.
• Current active alcohol or drug abuse or history of alcohol or drug abuse within 12 months prior to screening.
• Intolerance or contraindication to study therapies, including:
  • Evidence of intolerance or toxicity associated with tacrolimus prior to screening;
  • 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 and premedications;
  • Intolerance or hypersensitivity to tacrolimus and its excipients;
  • Lack of peripheral venous access. 
• Laboratory parameters:
  • AST or ALT 2.5 > the upper limit of normal (ULN);
  • Amylase or lipase > 2 x ULN;
  • Neutrophils < 1.5 x 10^3 /µL;
  • CD19+ B cells < 5/µL;
  • Positive for hepatitis B surface antigen (HBsAg) at screening.
  • Patients who are HBsAg negative and hepatitis B core antibody positive with no detectable hepatitis B virus (HBV) DNA will be allowed into the study but will require regular HBV DNA monitoring;
  • Positive hepatitis C virus (HCV) antibody at screening.
  • Patients with positive hepatitis C antibody test result with no detectable HCV RNA for at least 12 months after completion of antiviral therapy are eligible but will require regular HCV RNA monitoring;
  • Hemoglobin < 9 g/dL;
  • Platelet count < 75,000/µL;
  • Positive serum human chorionic gonadotropin measured at screening.

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

• Signed written informed consent in accordance to ICH-GCP and national/local regulation before any protocol-related procedures that are not part of normal patient care (for phase II part 2: part of normal patient care can be: e.g. CT or MRI, biopsy, determination of HPV-16 positivity by specified central laboratory).
• Female or male patients, aged at least 18 years (no upper limit of age for phase Ib and phase II part 1), 18 to 80 years of age (for phase II part 2).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
• Life expectancy of at least 3 months 5. Patients with histologically or cytologically documented metastatic or refractory/recurrent HPV16+ cancer (determined in an accredited central laboratory using a validated assay).
• Phase Ib and Phase II part 1: Patients with HPV-16+ cancers including oropharyngeal squamous cell carcinoma of the head and neck (SCCHN), cervical, vulvar, vaginal, penile, and anal cancer Phase II part 2: Patients with HPV-16+ cancers including cervical, vulvar, vaginal, penile, and anal cancer Disease MUST not be amenable to curative surgery resection or curative radiotherapy with documented disease progression after concertation with multidisciplinary board. 
• Phase Ib and Phase II part 1:
  • Patients MAY have received up to two prior lines of systemic chemotherapy for the management of metastatic or recurrent disease; for SCCHN, patients MUST have previously been exposed to platinum-based therapy, either as part of definitive chemo-radiation OR as first line systemic treatment for metastatic disease which may include cetuximab. Patients with recurrence/ progression within 6 months of prior multimodal therapy using platinum-based therapy are eligible.
  • Patients with cervical cancer may have undergone surgery and/or received definitive radiation or chemo-radiation therapy for localized disease.
  • Patients MUST have been exposed to platinum–based chemotherapy for metastatic disease which may include bevacizumab.
• Patients with platinum-refractory disease will be eligible Phase II part 2:
  • For recurrent/metastatic disease no more than one prior line of chemotherapy which can contain a platinum
    •Prior treatment for recurrent or metastatic disease is not required for:
  • Patients with recurrence/ progression within 6 months after completion of prior multimodal therapy for localized or locally advanced disease not amenable to curative treatment o Patients who are unsuitable for platinum-based therapy o Patients who refuse chemotherapy or other standard therapies for the treatment of metastatic or recurrent disease. The benefit of an immunotherapy over standard therapies must be validated by the medical board and duly documented. A minimum of 4 weeks interval should have elapsed between the completion of the last chemotherapy and study treatment start A minimum of 4 weeks interval between palliative bone directed radiotherapy and the start of the study treatment provided that radiation therapy does not affect the unique measurable lesion, if applicable.
• Phase II part 2: For patients with hepatic metastases
  •no more than 3 hepatic lesions in total (target and non-target lesions)
  •maximum size of hepatic target disease ≤ 30 mm according to RECIST 1.1.
• Phase Ib and Phase II part 1: Availability of tumor tissue from biopsy: at least 2 fresh tumor tissue samples are to be collected. Tumor tissue may come either from the local tumor or distant metastasis. Cytological material is not accepted Phase II part 2:
• Availability of archived or fresh tumor tissue for the determination of HPV-16 positivity. Patients must agree to undergo a core or excisional biopsy of a tumor lesion not previously irradiated (at least 2 fresh tissue samples to be collected). An archival sample obtained within one year prior to randomization is acceptable only if tumor is not accessible. Tumor tissue may come either from the local tumor or distant metastasis. Fine needle aspirates and bone biopsies are not adequate.
• At least one measurable lesion by CT scan according to RECIST 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy. 
• Adequate hematological, hepatic and renal function:
  • Hemoglobin ≥ 9.0 g/dL (for phase II part 2: without packed red blood cell transfusion within the prior 3 weeks);
  • Neutrophils ≥ 1.5x10^9 /L;
  • Total lymphocytes count ≥ 0.4x10^9 /L;
  • CD4 + ≥ 200 / µL;
  • Platelets count ≥ 100x10^9 /L.
  • Total bilirubin ≤ 1.5 x ULN;
  • Serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) ≤ 3 x ULN;
  • Glomerular Filtration Rate ≥ 50 mL/min (according to Modification of the Diet in Renal Disease (MDRD) formula or Cockroft & Gault formula);
  • Serum albumin ≥ 30 g/L.
• Negative blood pregnancy test at screening for women of childbearing potential.
• Highly effective contraception (i.e., methods with a failure rate of less than 1% per year) during the study period and for 3 months after the last study treatment administration for female patients of childbearing potential (WOCBP) and for male patients who are sexually active with WOCBP. Highly effective contraception methods are defined as:
  • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, intrauterine devices (IUDs) such as Mirena and Nonhormonal IUDs such as ParaGard for WOCBP patient or male patient’s WOCBP partner;
  • Tubal ligation;
  • Vasectomy In addition to highly effective contraception, participating male patients;
  • must use a condom during the study period and for 3 months after the last study treatment administration when engaging in any activity that allows for exposure to ejaculate;
  • must refrain from donating sperm.

• Prior exposure to cancer immunotherapy including cancer vaccines, any antibody/drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD-L1, anti-PD-1, or anticytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody 2.
  • Concurrent anticancer treatment within 28 days before the start of study treatment (e.g., chemotherapy, radiotherapy or cytokine therapy except erythropoietin);
  • Recurrent drainage procedures (once monthly or more frequently) for pleural effusion, pericardial effusion, or ascites 3. Major surgery within 28 days before the start of study treatment.
• Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to the first study treatment, with the exception of patients with adrenal insufficiency who may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
• Patients with central nervous system (CNS) metastases except those meeting the following criteria:
  • Brain metastases that have been treated locally and are clinically stable during 4 weeks prior to start of study treatment;
  • No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable).
• Other active malignancy requiring concurrent systemic intervention.
• Patients with previous malignancies other than the target malignancy to be investigated in this trial (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period  
• Patient with any organ transplantation, including allogeneic stem cell transplantation.
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTC V4.03 or V5.0 for phase II part 2), any history of anaphylaxis, or uncontrolled asthma.
• Any known allergy or reaction to eggs, gentamycin or attributed to compounds of similar chemical or biological composition to therapeutic vaccines/immunotherapeutic products . Any known allergy or reaction to any component of anti-PD-L1/PD-1 or its excipients.
• Patients with history of interstitial lung disease (phase Ib and phase II part 1).
• Patients with known history or any evidence of active interstitial lung disease / pneumonitis (phase II part 2).
•  Administration of a live vaccine within 28 days prior to the start of the study treatment.
• Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment.
• Patients with active, known, or suspected auto-immune disease or immunodeficiency, except type I diabetes mellitus, hypothyroidism only requiring hormone replacement or skin disorders (such as vitiligo, psoriasis) not requiring systemic treatment.
• Significant chronic or acute infectionsincluding infection with mpox and SARS-CoV-2 (COVID19) PCR positive testing.
• Positive serology for Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) or presence in the serum of the Hepatitis B surface antigens (HBsAg), at Baseline.
• Persisting toxicity related to prior therapy of Grade ≥ 2 NCI-CTCAE v4.03 or v5.0 for phase II part 2 (except neuropathy [see exclusion criterion below] and alopecia).
• Neuropathy ≥ Grade 3.
• Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction (< 6 months prior to enrollment), unstable angina pectoris, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication/active intervention, history of myocarditis (history of myocarditis for phase II part 2).
• Patient with any underlying medical condition that the treating physician considers might be aggravated by treatment or might impair the patient’s tolerance to study treatment.
• History of uncontrolled intercurrent illness including but not limited to:
  • Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or lower);
  • Uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%);
  • Uncontrolled infection (phase II part 2).
• Patients with pulse oximetry of less than 92% on room air (phase II part 2).
• Any psychological, familiar, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL).

Eligibility last updated 7/13/23. Questions regarding updates should be directed to the study team contact.

Stage 1 Key

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

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

General Eligibility Criteria:

• Assessment for general eligibility criteria is based on medical records of the site and interview with a candidate patient. Patients must meet ALL general inclusion criteria to participate in the clinical investigation. If ANY general exclusion criteria are met, the patient is excluded from the clinical investigation and cannot be enrolled.
• If any clinical and/or laboratory tests are required for patient screening and are not included in a site’s standard tests, they must be completed after written informed consent is obtained.

• Subject must have at least one of the clinical indications before device implant in adherence with ACC/AHA/HRS/ESC dual chamber pacing guidelines.
• Subject is ≥ 18 years of age or age of legal consent, whichever age is greater.
• Subject has a life expectancy of at least one year.
• Subject is willing to comply with clinical investigation procedures and agrees to return to clinic for all required follow-up visits, tests, and exams.
• Subject has been informed of the nature of the clinical investigation, agrees to its provisions and has provided a signed written informed consent, approved by the IRB/EC.

• Subject is currently participating in another clinical investigation that may confound the results of this study as determined by the Sponsor.
• Subject is pregnant or nursing and those who plan pregnancy during the clinical investigation follow-up period.
• Subject has presence of anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator’s opinion, could confound the assessment of the investigational device and/or implant procedure, limit the subject’s ability to participate in the clinical investigation or to comply with follow-up requirements of the clinical investigation results.
• Subject has a known allergy or hypersensitivity to < 1 mg of dexamethasone sodium phosphate or any blood or tissue contacting material listed in the IFU.
• Subject has an implanted vena cava filter or mechanical tricuspid valve prosthesis.
• Subject has pre-existing, permanent endocardial pacing or defibrillation leads (does not include lead fragments).
• Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device.
• Subject has an implanted leadless cardiac pacemaker (except for an Aveir ventricular LP).
• Subject is implanted with an electrically-active implantable medical device with stimulation capabilities (such as neurological or cardiac stimulators)*.
• Subject is unable to read or write.
  • * NOTE:  Does not apply to a medical device with no known impact to the Aveir Leadless Pacemaker System, including the Aveir Link Module. Patient evaluation and the decision to implant the LP should take into account the presence of other active implantable devices and should include consultation with the Sponsor and/or manufacturer of the co-existing device.

Eligibility last updated 11/18/21. Questions regarding updates should be directed to the study team contact.

• Patients ≥ 18 years old
• Patients undergoing POEM for:
  • Achalasia (types I, II, and III);
  • Non-achalasia esophageal motility disorders (e.g., diffuse esophageal spasm).
• POEM performed at Mayo Clinic by providers in the Division of Gastroenterology or the Division of Thoracic Surgery.

• Patients < 18 years old.
• Patients with prior POEM performed outside of Mayo Clinic.
• Prior upper gastrointestinal surgery.
• No authorization for research participation at Mayo Clinic.
• Inability to communicate/provide history of symptoms.

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

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

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

• Adults with unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer not amenable to curative therapy.
• Confirmed fibroblast growth factor receptor 2b (FGFR2b) overexpression by immunohistochemistry (IHC) (central testing result).
• Eastern Cooperative Oncology Group (ECOG) less than or equal to 1.
• Measurable, evaluable, or non-evaluable disease as long as evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Participant has no contraindications to mFOLFOX6 chemotherapy.
• Adequate organ and bone marrow function:
  • absolute neutrophil count greater than or equal to 1.5 times 10^9/L;
  • platelet count greater than or equal to 100 times 10^9/L;
  • hemoglobin greater than or equal to 9 g/dl;
  • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3 times the upper limit of normal (ULN) (or less than 5 times ULN if liver involvement).
  • total bilirubin less than 1.5 times ULN (or less than 2 times ULN if liver involvement); with the exception of participants with Gilbert's disease);
  • calculated or measured creatinine clearance (CrCl) of greater than or equal to 30 mL/minute calculated using the formula of Cockcroft and Gault -international normalized ratio (INR) or prothrombin time (PT) less than 1.5 times ULN except for participants receiving anticoagulation, who must be on a stable dose of anticoagulant therapy for 6 weeks prior to enrollment.

• Prior treatment for metastatic or unresectable disease.
  • Note: prior adjuvant or neo-adjuvant therapy for local disease is allowed if ended more than 6 months of 1st dose.
• Prior treatment with any selective inhibitor of fibroblast growth factor.
• ibroblast growth factor receptor (FGF-FGFR) pathway.
• Known human epidermal growth factor receptor 2 (HER2) positive.
• Untreated or symptomatic central nervous system (CNS) disease or brain metastases.
• Peripheral sensory neuropathy greater than or equal to Grade 2.
• Clinically significant cardiac disease.
• Other malignancy within the last 2 years (exceptions for definitively treated disease).
• Chronic or systemic ophthalmological disorders.
• Major surgery or other investigational study within 28 days prior to first dose of study treatment.
• Palliative radiotherapy within 14 days prior to the first dose of study treatment.
• Abnormalities of the cornea that may pose an increased risk of developing a corneal ulcer.

Eligibility last updated 10/22/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria Part 1 and Part 2:

- Adult with unresectable, locally advanced or metastatic (not amenable to curative
therapy) histologically documented gastric or gastroesophageal junction adenocarcinoma

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

- Measurable disease or non-measurable, but evaluable disease, according to Response
Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1)

- Participant has no contraindications to mFOLFOX6 chemotherapy or nivolumab

- Adequate organ function as follows:

- Absolute neutrophil count ≥ 1.5 x 10^9/L

- Platelet count ≥ 100 x 10^9/L

- Hemoglobin ≥ 9 g/dL without red blood cell (RBC) transfusion within 7 days prior
to the first dose of study treatment

- Aspartate aminotransaminase (AST) and Alanine aminotransaminase (ALT) <3 x upper
limit of normal (ULN) (or < 5 x ULN if liver involvement)

- Total bilirubin <1.5 x ULN (or < 2 x ULN if liver involvement or Gilbert's
disease)

- Calculated or measured creatinine clearance (CrCl) of ≥ 50 mL/minute calculated
using the formula of Cockcroft and Gault

- International Normalized Ratio (INR) or prothrombin time (PT) < 1.5 × ULN except
for participants receiving anticoagulation, who must be on a stable dose of
anticoagulant therapy for 6 weeks prior to enrollment

Additional Inclusion Criteria Part 2:

- No prior treatment for metastatic or unresectable disease except for a maximum of 1
dose of mFOLFOX6 with or without nivolumab. Prior adjuvant, neo-adjuvant, and
peri-operative therapy is allowed, provided it has been completed more than 6 months
prior to the first dose of study treatment

- Fibroblast growth factor receptor 2b (FGFR2b) ≥ 10% 2+/3+ tumor cells (TC) as
determined by centrally performed immunohistochemistry (IHC) testing, based on tumor
sample either archival (obtained within 6 months/180 days prior to signing
pre-screening informed consent) or a fresh biopsy.

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

Eligibility last updated 5/2/23. Questions regarding updates should be directed to the study team contact.

• Confirmed diagnosis of Crohn's disease (CD) for at least 3 months prior to Baseline.
• Crohn's disease activity index (CDAI) score 220
  •450 at Baseline.
• Confirmed diagnosis of moderate to severe Crohn's Disease as assessed by stool frequency (SF), abdominal pain (AP) score, and Simple Endoscopic score for CD (SES-CD).
• Demonstrated intolerance or inadequate response to one or more anti-tumor necrosis factor (TNF) therapies.

• Current diagnosis of ulcerative colitis or indeterminate colitis.
• Receipt of CD approved biologic agents prior to Baseline (as detailed in protocol), or any investigational biologic or other agent or procedure prior to Baseline (as detailed in protocol).
• Prior exposure to p19 and/or p40 inhibitors (e.g., risankizumab and ustekinumab).
• Currently know complications of CD (strictures, short bowel, etc).

• Signed informed consent.
• Age ≥ 18 years with life expectancy > 12 weeks.
• Histologically proven, newly diagnosed supratentorial glioblastoma based on the World Health Organization (WHO) classification (2016); prior diagnosis of lower grade astrocytoma that has been upgraded to histologically confirmed glioblastoma is eligible if chemotherapy and radiotherapy treatment-naïve.
• Randomization must occur within 5 weeks of resection (subjects undergoing biopsy only are excluded).
• Craniotomy site must be adequately healed, free of drainage or cellulitis and the underlying cranioplasty must appear intact prior to start of study treatment.
• Available and willing to submit sufficient and of adequate quality tumor tissue representative of glioblastoma to perform MGMT promoter methylation status testing.
• Karnofsky performance status (KPS) ≥ 60.
• Stable or decreasing corticosteroids within 5 days prior to study treatment start.
• Willing to forego the use of Tumor Treating Fields therapy (Optune®).
• Adequate organ function within 14 days prior to randomization:
• Bone marrow:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L;
  • Platelets count ≥ 100 x 10^9/L;
  • Hemoglobin ≥ 10 g/dL (eligibility level for hemoglobin may be met by transfusion).
• Renal:
  • Serum creatinine < 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution.
• Hepatic:
  • Total serum bilirubin ≤ 2 x ULN unless the patient has documented Gilbert syndrome;  
  • Aspartate and alanine transaminase (AST/SGOT and ALT/SGPT) ≤ 2.5 x ULN; ≤ 5.0 x ULN if there is liver involvement secondary to tumor;
  • Alkaline phosphatase (ALP) ≤ 2.5 x ULN; ≤ 5 x ULN in case of bone metastasis.
• Negative serum pregnancy test (for females of childbearing potential) within 14 days prior to randomization.
• Male and female subjects of reproductive potential must agree to use an effective method of contraception (e.g., oral contraceptives, intrauterine device, barrier method) throughout the study and for at least 3 months after the last dose of study treatment.
• Men are considered of reproductive potential unless they have undergone a vasectomy and confirmed sterile by a post-vasectomy semen analysis .
• Women are considered of reproductive potential unless they have undergone hysterectomy and/or surgical sterilization (at least 6 weeks following a bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusive procedure that has been confirmed in accordance with the device's label), have medically confirmed ovarian failure, or achieved postmenopausal status (defined as cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women.
• Willing and able to comply with protocol.

• Unable to swallow tablets or capsules.
• Pregnant or breastfeeding.
• Prior chemotherapy (including carmustine-containing wafers (Gliadel®), immunotherapy (including vaccine therapy)) or investigation agent for GBM or GS (previous 5-aminolevulinic acid [ALA]-mediated photodynamic therapy [PDT] administered prior to surgery to aid in optimal surgical resection is permitted).
• Prior radiotherapy to the brain.
• Unable to discontinue use of EIAEDs, if previously taking EIAEDs, must have been discontinued ≥ 2 weeks prior to randomization.
• Use of a strong inducer or moderate or strong inhibitor of CYP3A4 within 7 days prior to randomization or expected requirement for use on study therapy.
• Use of any medication that can prolong the QT/QTc interval within 7 days prior to randomization or expected requirement for use on study therapy.
• Active bacterial, fungal or viral infection requiring systemic treatment.
• Personal or immediate family history of long QT syndrome, QTc interval > 450 msec (males) or > 470 msec (females) at screening (recommended that QTc be calculated using Fridericia correction formula, QTcF), or a history of unexplained syncope.
• Any contraindication to temozolomide listed in the local product label.
• Another malignancy except adequately treated non-melanoma skin cancer; subjects who have had another malignancy in the past, but have been disease-free for more than 5 years, and subjects who have had a localized malignancy treated with curative intent and disease free for more than 2 years are eligible.
• Participation in other studies involving investigational drug(s) within 30 days prior to randomization.
• Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for participation in this study.

• Diagnosis of functional nasal obstruction or aesthetic nasal concern requiring nasal surgery with costal cartilage harvest.
• Male or female with age ≥ 18 years.
• Willing and able to understand and provide written informed consent.

• Age < 18 years of age.
• Known pregnancy.
• Women who are currently nursing a child.
• History of coagulopathy; such as hemophilia or Von Willebrand disease, or any congenital or acquired bleeding disorder.
• Use of anticoagulation medication during the study; i.e. aspirin, Coumadin, Plavix, or medications similar in class to these medications will exclude the patient from participation.
• Inability to provide informed consent (patients under guardianship).
• Known hypersensitivity to local anesthetics
• History of cardiac disease; such as current impaired cardiovascular function, past history of myocardial infarction, congenital heart disease, current cardiac symptoms; i.e. angina, shortness of breath, or chest pain as determined by history or review of the medical record.
• History of complex pulmonary disease; such as uncontrolled asthma, COPD, or interstitial lung disease as determined by history or review of the medical record. 
• Impaired renal function as documented in the medical record in the last 3 months with a serum creatinine greater than 1.2 mg/dL or glomerular filtration rate < 60 mL/min/BSA as determined by history or review of the medical record.
• History of or current hepatic disease as documented by liver function test abnormality in the last 3 months as determined by history or review of the medical record. 

Eligibility last updated 8/16/21. Questions regarding updates should be directed to the study team contact.

• Men and women aged 18 to 60 years.
• Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria.
• RRMS disease course as defined by the 2013 revisions of the MS clinical course definition.
• Participants must have evidence of active disease based on: one or more MS relapses within the last 18 months prior to screening visit or radiological evidence of MS activity (≥ 2 new T2 lesions within the last 12 months from screening [compared to a previous recent MRI within 18 months of screening] or ≥1 GdE demonstrated on brain or spinal cord MRI performed within the last 12 months of screening).
• Participants must be ambulatory with disease onset ≤ 5 years and treatment-naïve (i.e., no MS DMT at any time in the past).
• Participants must be eligible to receive at least one form of DMT within each treatment arm.
• EDSS at Baseline visit ≤ 6.5.

• Participants with contraindications to all forms of DMT in either of the treatment arms.
• Participants must never have received any of the following medications: natalizumab, alemtuzumab, ocrelizumab, rituximab, cladribine, siponimod, interferon beta-1a, interferon beta-1b, pegylated interferon beta-1a, glatiramer acetate, fingolimod, terflunomide, dimethyl fumarate, daclizumab, mitoxantrone.
• Participants must not have received any of the following medications, for reasons other than MS, in the last 12 months: cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, leflunomide, laquinimod, atacicept, other monoclonal antibodies (with the exception of antibodies directed at SARS-CoV-2).
• Participants with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study
• Participants unable to provide informed consent.
• Contraindication or inability to undergo MRI with Gd due to metal or metal implants, allergy to Gd contrast, claustrophobia, pain, spasticity, or excessive movement related to tremor.
• Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, mental, or social) that, in the opinion of the PI, is likely to affect the participant's ability to comply with the study protocol.

Eligibility last updated 4/28/22. 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: Elective surgical patients requiring non-emergent ultrasound-guided radial arterial catheter placement.
• Providers: Anesthesia providers to include trainees, certified registered nurse anesthetists (CRNA) and attending anesthesia providers.

• Patient
  • Age younger than 18 years or older than 85 years.
  • Pregnant.
  • Patients in a moribund state or palliative care only.
  • Vulnerable patients (i.e., Severe mental handicap, non-decisional).
  • History of peripheral arterial disease.
  • Placement of arterial catheter without ultrasound guidance.
• Provider: Medical students or CRNA students.

Eligibility last updated 8/17/21.  Questions regarding updates should be directed to the study team contact.

Inclusion Critieria:

• Suspicion for VEXAS syndrome based on the following being present.
• Current or historical elevated inflammatory markers (ESR > 20 mm/hr and/or CRP > 10 mg/L).
• PLUS at least one of the following inflammatory features present currently or historically:
  • Inflammatory arthritis;
  • Nasal or auricular chondritis;
  • Ocular inflammation (scleritis, episcleritis, uveitis);
  • Orbital / peri-orbital swelling/edema;
  • Cutaneous inflammation (inflammatory skin nodules, neutrophilic dermatosis, urticarial lesions, leukocytoclastic vasculitis);
  • Venous thromboembolism OR superficial thrombophlebitis;
  • Biopsy or radiographic confirmed evidence of vasculitis;
  • Inflammatory lung findings (multifocal ground glass opacity);
  • Recurrent fever, night sweats, unintentional weight loss.
• PLUS at least one of the following hematologic parameters:
  • MCV > 95 fl;
  • Anemia (hemoglobin < 13.2 g/dl for male or < 11.6 g/dl for female);
  • Thrombocytopenia (platelets < 135 x 10^9/L for male or < 157 x 10^9/L for female);
  • Leukopenia (white blood cell count < 3.4 x 10^9/L);
  • Neutropenia (neutrophil count < 1.56 x 10^9/L).

• Patients who are not able to provide informed consent.
• Patients < 18 years of age.
• Pregnancy.
• Patients who do not meet the above listed inclusion criteria.

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

Eligibility last updated 7/14/22. Questions regarding updates should be directed to the study team contact.

• Diagnosis of seropositive rheumatoid arthritis (either Rheumatoid factor or anti-CCP positive).
• Age-matched Healthy Controls.

• Chronic active viral infection.
• History of chemo/radiotherapy.
• History of cancer.
• Other autoimmune disease.
• Pregnancy.

Eligibility last updated 3/23/22. Questions regarding updates should be directed to the study team contact.

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

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

• Adults patients and children 5-17 years of age who undergo clininically indicated endovascular arterial or venous procedures by Interventional Radiology will be recruited.

• Adult patients who are unable to provide informed consent.

Eligibility last updated 8/17/22. Questions regarding updates should be directed to the study team contact.

• Adults ≥ 18 years of age.
• Admitted to the ICU.
• Must have the capacity to consent to video recording or have a legally authorized representative (LAR) or proxy to provide consent on their behalf.

• Individuals < 18 years of age.
• Unable to consent to study.
• Do not have a legally authorized representative (LAR) or proxy to provide consent on their behalf.

Eligibility last updated 1/24/22. Questions regarding updates should be directed to the study team contact.