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

Eligibility last updated 8/3/22. Questions regarding updates should be directed to the study team contact

• Ability to converse in English.
• Legal adult 18 years of age or older who have the capacity to consent to participating in this study.
• To meet Aims 1 and 2 and to ensure balanced stakeholder perspectives are gathered, eligible participants will be screened to identify employees of Mayo Clinic (currently employed by Mayo Clinic or employed by Mayo Clinic within the last five years) and non-employee (currently not employed by Mayo Clinic or employed by Mayo Clinic in the last five years).
• To meet the aims of this study, equilibrium of the number of eligible participants in the groups of the subject populations identified is desirable thus selective sampling of the groups will be implemented during recruitment

• Unable to converse in English.
• Individuals less than 18 years of age or who do not have the capacity to consent to participating in this study.
• Legally authorized representatives of contributors to the biobank
• To meet Aims 1 and 2, eligible participants in subject population group 1 will be screened to identify current participation in the Mayo Clinic Center for Individualized Medicine Biobank.
• Individuals who have donated to the Mayo Clinic.
• Biobank will be excluded from this study to safeguard an unbiased data collection on biospecimen research and perceptions of consent and voluntariness during a pandemic.

• Patients aged ≥ 40 years when signing the informed consent.
• Diagnosis: 
  • IPF based on 2018 ATS/ERS/JRS/ALAT Guideline [R18-2794] as confirmed by the investigator based on chest HRCT scan taken within 12 months of Visit 1 and if available surgical lung biopsy; and
  • UIP or probable UIP HRCT pattern consistent with the clinical diagnosis of IPF, as confirmed by central review prior to Visit 2*

*if indeterminate HRCT finding IPF may be confirmed locally by (historical) biopsy

• Stable for at least 8 weeks prior to Visit 1. Patients have to be either:
  • not on therapy with nintedanib or pirfenidone for at least 8 weeks prior to Visit 1 (combination of nintedanib plus pirfenidone not allowed); or
  • on stable* therapy with nintedanib or pirfenidone for at least 8 weeks prior to Visit 1 and planning to stay stable on this background therapy after randomisation.

[*stable therapy is defined as the individually and general tolerated regimen of either pirfenidone or nintedanib]

• Forced Vital Capacity (FVC) ≥ 45% of predicted normal at Visit 1.
• DLCO (corrected for haemoglobin [Hb] [Visit 1]) ≥ 25% to < 80% of predicted normal at Visit 1.
• Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.

• Relevant airways obstruction (pre-bronchodilator FEV1/FVC < 0.7) at Visit 1.
• In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
• Acute IPF exacerbation within 4 months prior to screening and/or during the screening period (investigator-determined).
• Lower respiratory tract infection requiring antibiotics within 4 weeks prior to Visit 1 and/or during the screening period.
• Major surgery (major according to the investigator’s assessment) performed within 3 months prior to Visit 1 or planned during the course of the trial. (Being on a transplant list is allowed).
• Any documented active or suspected malignancy or history of malignancy within 5 years prior to Visit 1, except appropriately treated basal cell carcinoma of the skin, “under surveillance” prostate cancer or in situ carcinoma of uterine cervix.
• Evidence of active infection (chronic or acute) based on clinical exam or laboratory findings at Visit 1 or at Visit 2.
• Any suicidal behaviour in the past 2 years (i.e., actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior).
• Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months or at Visit 1; i.e., active suicidal thought with method and intent but without specific plan; or active suicidal thought with method, intent and plan.
• Baseline condition or medical history of vasculitis.
• AST orALT > 1.5 x ULN or total Bilirubin > 1.5 x ULN at Visit 1.
• eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula or Japanese version of CKD-EPI for Japanese patients) ≤ 45 ml/min/1.73 m^2 at Visit 1.
  • Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results will be available only after randomisation. In case at Visit 2 the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is justified that the patient remains on study drug. The justification for decision needs to be documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error; i.e., there was no abnormal result of this test in the recent history of the patient and there is no related clinical sign, or the result of a temporary and reversible medical condition, once that condition is resolved.
• Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
• Cardiovascular diseases, any of the following:
  • Severe hypertension (uncontrolled under treatment ≥ 160/100 mmHg at multiple occasions) within 3 months of Visit 1;
  • Myocardial infarction within 6 months of Visit 1;
  • Unstable cardiac angina within 6 months of Visit 1.
• History of thrombotic event (including stroke and transient ischemic attack) within 6 months of Visit 1.
• Surgery of the GI tract that could interfere with PK of the trial medication (except appendectomy or simple hernia repair). day or any drug considered likely to interfere with the safe conduct of the trial.
• Patients not expected to comply with the protocol requirements or not expected to complete the trial as scheduled.
• Previous randomisation in this trial.
• Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s), or receiving other investigational treatment(s).
• In the opinion of the Investigator, active alcohol or drug abuse.
• Inability to refrain from smoking on trial days.
• Male patients who do not agree to minimize the risk of female partners becoming pregnant from first dosing day until 3 months after the study completion. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female partner (intra-uterine device with spermicide, hormonal contraceptive used for at least two months prior), true sexual abstinence (when
• this is in line with the preferred and usual lifestyle of the patient), or surgically sterilized, including vasectomy.
• Women who are not surgically sterilised or who are not postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of Follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory).
• History of allergy or hypersensitivity or contraindications to the class of drugs under study including known hypersensitivity to the drug or its excipients.
• Patients with a significant disease or condition other than IPF which in the opinion of the investigator, may put the patient at risk because of participation, interfere with study procedures, or cause concern regarding the patient’s ability to participate in the study or any medical condition which could lead to a life expectancy < 12 months.
• The patient has a confirmed infection with SARS-CoV-2 within the 4 weeks prior to Visit 1 and/or during the screening period.

Inclusion Criteria

• Diagnosis of MCD, FSGS, MN, or IgAN on first diagnostic kidney biopsy, per specified pathology definitions.
• First diagnostic kidney biopsy within 5 years of study enrollment.
• Access to first kidney biopsy report and/or slides.
• All ages.
• Willing to comply with study requirements, including intention to fully participate in protocol-specified follow-up at a clinical study site.
• Informed consent and, where age appropriate, informed assent.

 Exclusion Criteria

• ESKD, defined as chronic dialysis or kidney transplant.
• Institutionalized.
• Solid organ or bone marrow transplant recipient at time of first kidney biopsy.
• Diagnosis of any of the following at the time of first diagnostic kidney biopsy:
  • Diabetes mellitus;
  • Histopathologic findings of diabetic glomerulosclerosis;
  • Systemic lupus erythematosus;
  • HIV infection;
  • Active malignancy, except for non-melanoma skin cancer;
  • Active Hepatitis B or C infection, defined as positive viral load.

• Histological or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting.
• Initial diagnosis of metastatic disease must have occurred ≤ 6 weeks prior to screening.
• Subject has one or more metastatic tumours measurable by computed tomography (CT) scan (or magnetic resonance imaging (MRI), if the subject is allergic to CT contrast media) according to RECIST Version 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Subject has adequate biological parameters as demonstrated by the following blood counts:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3 without the use of hemopoietic growth factors within the last 7 days prior to randomisation;
  • Platelet count ≥100,000/^;
  • Haemoglobin (Hgb) ≥ 9 g/dL obtained ≤ 14 days prior to randomisation.
• Adequate hepatic function as evidenced by:
  • Serum total bilirubin ≤ 1.5 x ULN (biliary drainage is allowed for biliary obstruction); and
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) (≤ 5 x ULN is acceptable if liver metastases are present).
• Adequate renal function as evidenced by creatinine clearance ≥ 30 mL/min.
• Adequate coagulation studies (obtained ≤ 14 days prior to randomisation) as demonstrated by prothrombin time and partial thromboplastin time within normal limits (≤ 1.5 x ULN ).

• Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy.
• Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant setting, except those where at least 12 months have elapsed since completion of the last dose and no persistent treatment-related toxicities are present.
• Subject has only localised advanced disease.
• Documented serum albumin < 3 g/dL.
• Known history of central nervous system (CNS) metastases.
• Clinically significant gastrointestinal disorder.
• History of any second malignancy in the last 2 years.
• Concurrent illnesses that would be a relative contraindication to trial participation.
• Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1.
• Neuroendocrine (carcinoid, islet cell) or acinar pancreatic carcinoma.

PRE-REGISTRATION

• Histological confirmation of a pancreatic malignancy as confirmed by the local pathology lab.
• Patients whose disease has progressed on (or who were intolerant of) at least one line of therapy for metastatic disease.
• Patients whose disease has recurred with metastatic disease:
  • ≤ 12 weeks of completion of neoadjuvant or adjuvant systemic chemotherapy; or
  • Patients with locally advanced disease whose disease progressed to metastatic disease on; or
  • ≤ 12 weeks after completion of systemic chemotherapy would also be eligible.
• Provide informed written consent ≤ 28 days prior to pre-registration.
• Central electronic/paper confirmation of the presence of a BRAF V600E mutation. This review is mandatory prior to pre-registration to confirm eligibility. Results from a Clinical Laboratory Improvement Act (CLIA)/College of American Pathologists (CAP) certified testing lab (commercial or institutional) that confirm the presence of a BRAF V600E mutation in the patient's tumor must be submitted for central review

REGISTRATION 

• Registration must occur ≤ 30 days after pre-registration.
• Confirmation of the presence of BRAF V600E mutation in the patient's tumor.
• Measurable disease.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2. (Form is available on the Academic and Community Cancer Research United [ACCRU] web site).
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained 14 days prior to registration).
• Platelet count ≥ 75,000/mm^3 (obtained ≤ 14 days prior to registration).
• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 14 days prior to registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration).
• Aspartate transaminase (AST) ≤ 2.5 x ULN; in participants with liver metastases ≤ 5 x ULN (obtained ≤ 14 days prior to registration).
• Aminotransferase (ALT) ≤ 2.5 x ULN; in participants with liver metastases ≤ 5 x ULN (obtained ≤ 14 days prior to registration).
• Calculated creatinine clearance must be ≥ 45 ml/min using the Cockcroft Gault formula (obtained ≤ 14 days prior to registration).
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
  • Note: During the active monitoring phase of a study (i.e., active treatment), participants must be willing to return to the consenting institution for follow-up.
• Ability to swallow the investigational product tablets and capsules.
• Willing to provide tissue and blood samples for correlative research purposes.

REGISTRATION

• Patients whose tumor harbors a BRAF non-V600E mutation or a BRAF fusion.
• Prior therapy with BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib).
• Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
    • NOTE: Female participants of childbearing potential must agree to use methods of contraception that are highly effective or acceptable, and to not donate ova from screening until 30 days after the last dose of study drug.
    • NOTE: Male participants must agree to use methods of contraception that are highly effective or acceptable, and to not donate sperm from screening until 90 days after the last dose of study drug.
• 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.
  • NOTE: Patients known to be human immunodeficiency virus ( HIV) positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to registration.
• Left ventricular ejection fraction (LVEF) ≤ 50% as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
• Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150/100 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
• Triplicate average baseline corrected QT (QTc) interval ≥ 480 ms.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Patients who have had another active malignancy within the past two years are ineligible EXCEPT FOR patients with cervical cancer in situ, in situ carcinoma of the bladder, non-melanoma carcinoma of the skin, or patients who have had therapy with curative intent for breast or prostate cancer, but remain on adjuvant hormonal therapy.
• Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic biologic therapy (e.g., erlotinib, cetuximab, bevacizumab etc.), ≤ 14 days (≤ 28 days for an antibody-based therapy) prior to registration.
• Patients who have undergone major surgery (e.g., in-patient procedures) ≤ 6 weeks prior to registration or who have not recovered from side effects of such procedure.
• Patients who have had radiotherapy ≤ 14 days prior to registration or who have not recovered from side effects of such procedure.
  • NOTE: Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment.
• Patient has not recovered to ≤ grade 1 from toxic effects of prior therapy before registration.
  • EXCEPTIONS: Stable chronic conditions (≤ grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies).
• Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis that are not stable, require steroids, are potentially life-threatening or have required radiation ≤ 28 days prior to registration.
  • NOTE: Patients with previously treated brain metastases may participate provided they are stable (e.g., without evidence of progression by radiographic imaging for ≤ 28 days prior to registration and neurologic symptoms have returned to baseline), and have no evidence of new or enlarging brain metastases or central nervous system (CNS) edema, and does not require steroids at least 7 days before the first dose of study treatment.
• Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (≤ 12 weeks) history of a partial or complete bowel obstruction, or other condition that will interfere significantly with the absorption or oral drugs.
• Known history of acute or chronic pancreatitis.
• Concurrent neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amytrophic lateral sclerosis, spinal muscular atrophy).
• History or current evidence of RVO or current risk factors for retinal vein occlusion (RVO) (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
• Current use of prohibited medication (including herbal medications, supplements, or foods), or use of prohibited medication ≤ 7 days prior to registration.
• History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to registration. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e., massive or sub-massive) deep vein thrombosis or pulmonary emboli.
  • NOTE: Patients with either deep vein thrombosis or pulmonary emobli that do not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for ≤ 4 weeks prior to registration.
  • NOTE: Patients with thromboembolic events related to indwelling catheters or other procedures may register.
• Evidence of hepatitis B Virus (HBV) or hepatitis C Virus (HCV) infection.
  • NOTE: Patients with laboratory evidence of cleared HBV or HCV infection may register.
  • NOTE: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may register.

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

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

• Patients
  • Consult telehealth appointment conducted by phone or video with surgeon and patient before surgery.
  • Willing to complete a feedback survey.
  • Telehealth visit in the department of BEMGI, THS, HPB, or PLS at Mayo Clinic Rochester.
  • Expected to undergo surgery in the departments listed above.
• Surgeons
  • A Surgeon  in the Department of BEMGI, THS, HPB, or PLS at Mayo Clinic Rochester.
  • 2-3 Surgeon  per division that have prior experience with video visits.
  • Willing to complete  all study activities.

• Patients
  • Under the age of 18.
  • Not willing to complete a feedback survey.
  • Not receiving an appointment in the Department of BEMGI, THS, HPB, or PLS at Mayo Clinic Rochester.
• Surgeons
  • Not a Surgeon in the Department of BEMGI, THS, HPB, or PLS at Mayo Clinic Rochester.
  • Not willing to complete all study activities.

• Signed informed consent prior to any study specific procedures.
• Male or female subject.
• Age ≥ 18.
• Symptoms of dyspnea (NYHA II-III) with no non-cardiac or ischemia explanation.
• EF ≥ 50%.
• Elevated pulmonary capillary wedge pressure (PCWP) during exercise (≥ 25 mmHg) ascertained at Visit 1. Patients that have consented to study procedures but do not meet this invasive criterion will be considered as screen failures and will not be randomized.

• Type I diabetes.
• Type II diabetes with poor control (HgbA1c ≥ 10%).
• Recent hospitalization (< 30 days) or revascularization (< 90 days).
• Primary cardiomyopathy (such as amyloid).
• Constrictive pericarditis.
• Dyspnea due to primary lung disease or myocardial ischemia in the opinion of the investigator.
• Severe anemia (hemoglobin < 9 gm/dl).
• Significant left-sided valvular heart disease (> moderate stenosis, > moderate regurgitation).
• Severe kidney disease (estimated GFR < 30) or liver disease.
• Women of child bearing potential not willing to use a medically accepted method of contraception OR who are currently pregnant (confirmed with positive pregnancy test) or breast feeding.
• History of serious hypersensitivity reaction to dapagliflozin.
• Subjects on dialysis.
• Subjects with severe hepatic impairment (Child-Pugh class C).
• Currently taking Empagliflozin or Canagliflozin.

Eligibility last updated 8/25/21. Questions regarding updates should be directed to the study team contact.

• Age 18-70 years old
• No known coronary artery disease, brochospastic disorders or coagulopathies.
• Negative COVID-19 screening and molecular testing.
• Able to give informed consent.

• Age under 18 and over 70 years old.
• Inability to receive sedation or anesthesia (if required for the procedure).
• Emergency procedures.

• Has provided informed consent (signed by study patient or legally acceptable representative).
• Male or female adult ≥ 18 years of age (or country’s legal age of adulthood) at randomization.
• Laboratory-confirmed SARS-CoV-2 infection as determined by a RT-PCR result from any specimen (or other commercial or public health assay) ≤ 72 hours from randomization and no alternative explanation for current clinical condition.
• COVID-19 symptom onset ≤ 7 days.
• Hospitalized for COVID-19 illness for < 72 hours with at least 1 of the following at randomization; patients meeting more than one criterion will be categorized in the most severely affected category:
  • Cohort 1: Maintains O2 saturation > 93% on low-flow oxygen via nasal cannula, simple face mask, or other similar device;
  • Cohort 2: High-intensity oxygen therapy without mechanical ventilation, where high-intensity is defined as receiving supplemental oxygen delivered by 1 of the following devices:
    • Non-rebreather mask (with an SpO2 ≤ 96% while receiving an oxygen flow rate of at least 10 L/min).
    • High-flow device (e.g., AIRVO™ or Optiflow™) with at least 50% FiO2.
    • Non-invasive ventilator, including continuous positive airway pressure (CPAP), to treat hypoxemia (excluding isolated use for sleep-disordered breathing).
  • Cohort 3: On mechanical ventilation

• Phase 1 only: Patients maintaining O2 saturation > 94% on room air.
• In the opinion of the investigator, unlikely to survive for > 48 hours from screening.
• Receiving extracorporeal membrane oxygenation (ECMO).
• Has new-onset stroke or seizure disorder during hospitalization.
• Initiated on renal replacement therapy due to COVID-19.
• Has circulatory shock requiring vasopressors at randomization.
  • Note: Patients who require vasopressors for sedation-related hypotension or reasons other than circulatory shock may be eligible in this study.
• Patients who have received convalescent plasma or IVIG in the past 5 months or plan to receive during the study period for any indication.
• Participation in a clinical research study, including any double-blind study, evaluating an investigational product within 30 days and less than 5 half-lives of the investigational product prior to the screening visit.
  • Note: The use of remdesivir, hydroxychloroquine, or other treatments (except for COVID- 19 convalescent plasma or IVIG) being used for COVID-19 treatments in the context of the local standard-of-care or an open-label study or compassionate use protocol is permitted.
• Any physical examination findings, history of illness, and/or concomitant medications that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study.
• Known allergy or hypersensitivity to components of study drug.
• Pregnant or breastfeeding women.
• Continued sexual activity in women of childbearing potential (WOCBP)* or sexually active men who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose.
• Highly effective contraceptive measures in women include:
  • Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
  • Intrauterine device (IUD);
  • Intrauterine hormone-releasing system (IUS);
  • Bilateral tubal ligation;
  • Vasectomized partner,† and/or;
  • Sexual abstinence‡,§;
  • Male study participants with WOCBP partners are required to use condoms unless they are vasectomized† or practice sexual abstinence.‡,§.

* WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

† Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success.

‡ Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

§ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.

• Adults age 18 years or older.
• Currently scheduled to undergo a nuclear medicine exam.

• Individuals under 18 years of age.
• Unwilling/unable to sign an informed consent form.
• Unable to lie on a Veriton imaging table for up to 40 minutes.

• Informed consent signed by the patient.
• ≥ 18 years of age.
• Confirmed diagnosis of symptomatic MM per IMWG criteria.
• Measurable disease as defined by one or more of the following:
  • Serum M-protein ≥ 0.5 g/dL;
  • Urine M-protein ≥ 200 mg/24 hours;
  • Serum free light chain (FLC) assay: involved FLC level ≥ 10 mg/dL provided serum FLC ratio is abnormal;
  • In cases where SPEP is unreliable, serum quantitative immunoglobulin (qIgA) ≥ 500 mg/dL (0.5 g/dL) is acceptable;
  • In patients with non-secretory disease, bone marrow plasmacytosis of ≥ 30%. Patients must have bi-dimensional measurable disease.
• Relapsed or refractory [Rajkumar 2011] to at least 3 prior systemic lines of therapy for MM, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), chemotherapies, or monoclonal antibodies, and not a candidate for, or intolerant to established therapy known to provide clinical benefit:
  • Relapse defined as progression of disease after an initial response (MR or better) to previous treatment, more than 60 days after cessation of treatment;
  • Refractory disease defined as < 25% reduction in M-protein or progression of disease during treatment or within 60 days after cessation of treatment;
  • Progressed on the final line of therapy received before being considered for this study.
• If not menopausal or surgically sterile (female and male), patients must be willing to practice at least two highly effective methods of birth control for at least one of their or their partner’s menstrual cycle before and for 3 months after study drug administration.
• Eastern Cooperative Oncology Group status 0-1.
• Resolution of prior therapy-related AEs (including immune-related AEs but excluding alopecia) to ≤ Grade 1 (except for Grade 2 peripheral neuropathy) per CTCAE.
• Minimum of 2 weeks or 5 half-lives since last dose of other systemic cancer therapy or radiotherapy. Palliative radiation to localized sites is permitted in Phase 2.
• Adequate organ function as indicated by the following lab values:
• Hematological:
  • Neutrophils ≥ 1,000/µL;
  • Platelets ≥ 100,000/µL;
  • Hemoglobin* ≥ 9g/dL.
• Renal:
  • eGFR (CKD-EPI calculation) ≥ 30 mL/min/1.73m^2.
• Hepatic:
  • Serum total bilirubin ≤ 1.5 x ULN; or
  • Direct bilirubin ≤ ULN for patients with total bilirubin >1.5 x ULN.

Exception for elevated bilirubin secondary to Gilbert’s disease. Confirmation of Gilbert’s diagnosis requires: elevated unconjugated (indirect) bilirubin values; normal CBC in previous 12 months), blood smear and reticulocyte count; normal transaminases and alkaline phosphatase in previous 12 months.

• AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases.
  Transfusion and/or erythropoietin not permitted within 1 week prior to blood draw

• Patient consents to a fresh bone marrow biopsy at screening (once all other entry criteria have been satisfied).
• Patient consents to a potential on-treatment bone marrow biopsy.
• Able and willing to comply with the protocol and the restrictions and assessments therein.

• < 18 years of age.
• Monoclonal gammopathy of undetermined significance, smoldering myeloma, Waldenstrom’s macroglobulinemia.
• History of plasma cell leukemia.
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome.
• Previous Grade 3-4 infusion or hypersensitivity reaction (not immunotoxicity) to treatment with another mAb.
• Previous history of severe asthma, or within the past year, history of exacerbations of chronic obstructive pulmonary disease requiring either hospital admission or steroids.
• History of clonal mast cell disorder.
• Hereditary alpha tryptasemia (Screening tryptase result must be available prior to starting AO-176 study drug).
• Prior treatment with a checkpoint inhibitor (anti-PD-1, PD-L1, CTLA-4, etc.) within 4 weeks.
• Prior treatment with a therapeutic agent that targets the CD47 axis.
• Autologous stem cell transplant, chimeric antigen receptor T-cell treatment, or bone marrow transplant within 12 weeks prior to first dose of study drug.
• Platelet or RBC transfusion within 1 week of Screening blood draw.
• Patients at high thrombotic risk in whom antithrombotic medications cannot be withheld for short periods. These include, but are not limited to, patients with a history of multiple or clinically severe venous thromboembolism (VTE), or a severely hypercoagulable condition such as antiphospholipid antibody syndrome. Patients receiving dual antiplatelet therapy (DAPT) are excluded.
• Prior organ transplant.
• History of autoimmune hemolytic anemia or autoimmune thrombocytopenia.
• History of any condition known to be associated with reduced RBC lifespan (e.g., thalassemia trait, G6PD deficiency).
• History of Evans syndrome.
• Active autoimmune disease or history of severe allergic diathesis or anaphylaxis.
• Bleeding diathesis, or other known risk for acute blood loss.
• Known active central nervous system myeloma.
•  Active known second malignancy with the exception of any of the following:
  • Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer;
  • Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for ≥ 2 years;
  • Low-risk prostate cancer with Gleason score 350/mm^3 and undetectable viral load) are eligible.
• Current active liver disease from any cause, including hepatitis A (hepatitis A virus IgM positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative.
• Use of systemic corticosteroids (> 10 mg prednisone or equivalent) within 15 days (except for prophylaxis for radiodiagnostic contrast reactions), or other immunosuppressive drugs within 30 days, prior to start of the study (except for IRR prophylaxis).
• Phase 1 Part 1 Expansion (Cohort 1E), Phase 1 Part 2 (Cohorts 2A, 2B), and Phase 2 Part 2 only:
  • Presence of condition for which dexamethasone is contraindicated (e.g., active viral or fungal disease, uncontrolled psychoses, receipt of live viral vaccine in prior 30 days); or
  • Prior adverse reaction or intolerance to dexamethasone that resulted in treatment discontinuation.
• Receipt of an investigational product or been treated with an investigational device within 30 days prior to first drug administration.
• Any of the following within 6 months before Baseline Day 1:
  • Myocardial infarction;
  • Unstable angina;
  • Unstable symptomatic ischemic heart disease;
  • New York Heart Association Class III or IV heart failure;
  • Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events);
  • Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease).
• Electrocardiogram (ECG) QT interval corrected for heart rate (QTc) > 480 msec, measured by Fridericia's formula [QTcF = QT/(RR^0.33)]. If the QTc is prolonged in a patient with a pacemaker or bundle branch block, the patient may be enrolled in the study if confirmed by the Medical Monitor.
• Any other medical or psychiatric condition that, in the opinion of the Investigator, would compromise patient safety, or interfere with the objectives of the protocol or completion of treatment per protocol.
• Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of participation in the study.
• Phase 1 Part 2 (Cohorts 2A and 2B), and Phase 2 Part 2 only: patients with a history of bortezomib hypersensitivity.
• Phase 1 Part 2 (Cohorts 2A and 2B) and Phase 2 Part 2 only: patients with a history of bortezomib-related hypotension. (Hypotension, as indicated by systolic blood pressure 20 mmHg decrease in systolic blood pressure 1 minute or more after assuming upright position).
• Phase 1 Part 2 (Cohorts 2A and 2B) and Phase 2 Part 2 only: use of St. John’s Wort within 2 weeks prior to Cycle 1 Day 1.

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

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

• Age ≥ 18 years old.
• Diagnosis of SEA by a health care provider
• History of an absolute eosinophil count ≥ 300/mm^3
• Prescription for mepolizumab provided during course of routine clinical care but mepolizumab not yet started

• Age < 18 years old.
• Pregnancy.
• Currently using or have used within 3 months of the initial baseline visit any biologic or immunomodulatory therapy with the exception of #3.
• Currently using or any prior use of rituximab.
• History of upper/lower respiratory tract infection or asthma exacerbation within the previous four weeks of the first baseline visit.
• Any prior history of malignancy, autoimmune disease, or immune deficiency.
• Any other significant medical issue as determined by the principal investigator.

• Patients must have a pathogenic variant in the NF2 gene (either in the germline or in two NF2-related tumors) OR a confirmed diagnosis of NF2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria.  The NIH criteria18 includes presence of:
  • Bilateral vestibular schwannomas; OR
  • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.
• The Manchester criteria19 includes presence of:
  • Bilateral vestibular schwannomas; OR
  • First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity; OR
  • Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity; OR
  • Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR any two of: schwannoma, glioma, neurofibroma, cataract.
• Participants must have a target NF2-related tumor (VS, non-VS, meningioma, or ependymoma) with documented radiographic progression within the preceding 36 months of Master Study registration defined as either:
  • ≥ 20% increase in volume of enhancing tumor;
  • ≥ 2 mm increase in greatest linear dimension of enhancing tumor.
• Participants must have measurable disease, defined as:
  • VS, non-VS, or meningioma target lesions that can be accurately measured as ≥1 ml by volumetric MRI scan or in at least one dimension as ≥10 mm with conventional MRI scan. 
• Ependymoma target lesions measurable linearly. 
• Participant must have a target NF2-related tumor with the following qualities:
  • Not amenable to surgery due to patient refusal or due to high risk for surgical complications (e.g., damage to nerve function).
• Participant must be ≥ 12 years of age on Day 1 of treatment.
• Life expectancy of greater than 1 year.
• For participants 16 or older: Karnofsky performance status ≥ 70 or ECOG PS 0 or 1; for participants age 12 to < 16: Lansky scale ≥ 70.
• Ability to understand and the willingness to sign written informed consent and assent documents.
• Must have established relationship with primary care physician and provide contact information.

• Participants who have had chemotherapy within a minimum of 4 weeks prior to Master Study registration (or a minimum of 5 half-lives and resolution to baseline of toxicities unless there are irreversible toxicities from prior drug that do not influence risk of next drug). 
• Participants who have received radiation to the target tumor within the last 3 years prior to Master study registration.
• Participants who are receiving any other investigational agents.
• Participants with target or non-target nervous system tumors that, in the opinion of the treating investigator, are likely to require active treatment (including surgery) within 6 months of registration to the Master Study.
• History of a different malignancy, unless:
  • have been disease-free for at least 2 years and are deemed by the treating investigator to be at low risk for recurrence of that malignancy; and/or
  • malignancy was breast or cervical cancer in situ, superficial bladder cancer or basal cell or squamous cell carcinoma of the skin, and malignancy has been treated. Patients who meet the above listed criteria and are only on preventative treatment will be deemed eligible.
• Pregnant women are excluded from this study because the experimental agents may have the potential for teratogenic or abortifacient effects.  Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these experimental agents, breastfeeding should be discontinued if the mother is treated.

Eligibility last updated 8/20/21.  Questions regarding updates should be directed to the study team contact.

• Patients ≥ 18 years of age.
• Both males and females.
• Underwent any kind of valve replacement surgery, bioprosthetic or mechanical, at any position, either implanted surgically or percutaneously.
• Underwent valve replacement therapy over the past 10 years.

• Patients under 18 years of age.

• Women who participate in the parent SCORE studies (IRB 18-008476).

• Night shift workers will be excluded.

• Mayo Clinic patients with suspected COVID-19 including those who test positive or negative for SARS-CoV-2.
• All patients 18 years of age and older will be eligible.
• All racial and ethnic groups are eligible. 

• Individuals under 18 years of age.

• Adults (≥ 18 years old).
• Patients at Mayo Clinic Arizona and Mayo Clinic Minnesota who participated in spinal cord stimulator trial from January 2010 to December 2019.
• Patients who subsequently underwent permanent implantation of spinal cord stimulator.
• These subjects will be contacted via e-mail or telephone to complete a standardized “yes/no” questionnaire to assess current SCS usage, effectiveness of their implant, overall satisfaction, as well as determine how many patients underwent explantation.

• Individuals under 18 years old.
• Did not participate in spinal cord stimulator trial nor undergone spinal cord stimulator implantation between January 2010 and December 2019.

Inclusion Criterion:

• Patients age 13-22 years.
• Patients atttending the PRC 3 week program.
• Patients who have been diagnosed with POTS.

Exclusion Criterion:

• Patients< age 13 or > 22 years.
• Lack of assent from the child to participate/wear actigraph/answer brief questionnaire.

• Have signed the current approved informed consent form.
• Have a clinically or phenotypically defined VM, LM, or mixed VLM affecting the skin.
• Lesion genotyping confirms either PIK3CA or TEK mutations, known to be pathogenic.
• Agrees to use contraception if of childbearing potential.
• Willing and able to comply with the protocol and be available for the entire study.
• Between 18 and 60 years of age.
• Lesion must be amenable to defining a contiguous study treatment area of 140 cm^2.

• Lesion to be treated is on the face or involves mucosa.
• Presence of ulcerations on the target-treatment lesion.
• Known systemic hypersensitivity to the VT30 drug substance, its inactive ingredients, or the vehicle.
• Uncontrolled diabetes mellitus.
• Hyperlipidemia that is poorly controlled on current treatment.
• Pregnant or nursing, planning to become pregnant, or planning to father a child during the study.
• History of malignancy except successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix.
• Major surgery within 8 weeks of Screening, or a surgical, laser or other procedure involving the target lesion within 8 weeks of Screening, or planned to occur during the study.
• Any other medical or personal condition that, in the opinion of the Investigator, may potentially compromise the safety or compliance of the subject, or may preclude the subject's successful completion of the clinical study.
• Medically significant infection (e.g., cellulitis or abscess, or a systemic infection) within 8 weeks of Screening.
• Ongoing therapy with another topical treatment or any medication that inhibits PI3K, Akt pathway, or the mTOR pathway, or in the opinion of the Investigator, the subject requires systemic therapy for their vascular malformation condition.
• Use of a biologic or systemic immunosuppressive agent within 3 months of Screening.
• Systemic use of corticosteroids, within 30 days of Screening.
• Treatment with a small molecule investigational product within 30 days of Screening, or with any investigational biologic products within 3 months of Screening.
• Positive for hepatitis C antibody, hepatitis B surface antigen, hepatitis B core antibody, or human immunodeficiency virus.
• Alanine transaminase or aspartate transaminase laboratory values in excess of 1.5 x the upper limit of normal at Screening.
• Hemoglobin A1c is > 8%.
• Any other clinically significant laboratory or testing abnormality that, in the opinion of the Investigator, might confound the study, interfere with the subject's ability to complete the study, or represent a meaningful safety risk upon study enrollment.

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

Inclusion Criteria

- Age >18

- Able to provide written informed consent and willing to participate in all required
study follow-up assessments

- Symptomatic CAD with refractory angina defined as CCS class II to IV, despite optimal
tolerated medical therapy

- Abnormal coronary microvascular function indices: CFR≤2.5 and/or IMR≥25

Exclusion Criteria

- Recent (within 3 months) acute coronary syndrome

- Patients with prior coronary artery bypass surgery

- Unstable angina (recent onset angina, crescendo angina, or rest angina with ECG
changes) during the last 30 days

- Subjects in cardiogenic shock (systolic pressure < 80mm/Hg, on vasopressors or
intraaortic counter pulsation) at the time of consenting. Subjects who recover from
cardiogenic shock by the time of consenting are eligible.

- Obstructive CAD on coronary angiography (>70% stenosis or 50-70% stenosis with
iFR<0.89 or FFR<0.8 in epicardial artery)

- Inability to perform invasive coronary flow evaluation and/or measure CFR and IMR in
the LAD

- Severe valvular heart disease

- LVEF<30%

- Decompensated congestive heart failure (CHF) or hospitalizatoin due to CHF during the
last 3 months

- Patient with a pacemaker electrode in the CS

- Mean right atrial pressure >15 mmHg

- Anomalous or abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left
superior vena cava (SVC) as demonstrated on angiogram

- CS diameter at the site of planned implantation greater than 13mm or less than 9.5 mm
as measured by angiogram

- Severe chronic obstructive pulmonary disease (COPD) indicated by a forced expiratory
volume in one second that is less than 55 percent of the predicted value

- Tricuspid valve replacement or repair (tissue or mechanical)

- Chronic renal failure (serum creatinine >2mg/dL), and or on chronic hemodialysis

- Moribund, or with comorbidities limiting life expectancy to less than one year

- Known severe reaction to required procedural medication

- Known allergy to stainless steel or nickel

- Magnetic Resonance Imaging (MRI) within 8 weeks of Reducer implantation

- Participation in another ongoing investigational trial

- Additional factors deemed unsuitable for trial enrollment per discretion of principal
investigator

- Inmates

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

Eligibility last updated 10/5/22. Questions regarding updates should be directed to the study team contact

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

Eligibility last updated 9/12/22. Questions regarding updates should be directed to the study team contact.

• Adults ≥ 18 years of age.
• Bladder tumor on pre-biopsy cystocopy.
• High suspicion for bladder cancer.

• Under 18 years of age.

• Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Male or female subjects 18 years or older.
• Patients must have a diagnosis of morphologically documented AML or secondary AML [from prior conditions, such as myelodysplastic syndrome (MDS), or therapy-related AML (t-AML), as defined by World Health Organization (WHO) criteria.
• During the dose-escalation phase, only subjects with relapsed/refractory AML will be eligible (patients who have received prior AML therapy and have ≥ 5% blasts ).
• During the expansion phase, subjects with relapsed/refractory AML will be eligible OR subjects with newly diagnosed AML unable or unwilling to receive intensive induction chemotherapy will be eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Clinical laboratory values within the following parameters:
  • Albumin > 2.7 g/dL;
  • Total bilirubin ≤ institutional upper limit of normal (ULN). Patient with total bilirubin > ULN may enroll if direct bilirubin ≤1.5 x institutional ULN of the direct bilirubin;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × institutional ULN;
  • Creatinine clearance ≥ 30 mL/min (calculated by Cockcroft-Gault formula);
  • White blood cell (WBC) count < 25,000/μL before administration of pevonedistat on cycle 1 day 1;
    • Note: Hydroxyurea may be used to meet this criterion.
  • Prothrombin time (PT) and partial thromboplastin time (PTT) < 1.5 institutional ULN.
• Female subjects who:
  • Are postmenopausal for at least one year before the screening visit; OR
  • Are surgically sterile; OR
  • If they are of childbearing potential:
    • Agree to practice one highly effective method and one additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through four months after the last dose of study drug (female and male condoms should not be used together); OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception).
• Male subjects, even if surgically sterilized (i.e., status postvasectomy), who:
  • Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through four months after the last dose of study drug (female and male condoms should not be used together); OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

• Acute promyelocytic leukemia.
• Extramedullary only relapse AML.
• Treatment with systemic antineoplastic therapy or radiation within 14 days before the study enrollment. The use of hydroxyurea for leukoreduction is permitted. Subjects must have recovered from the side effects of prior therapy per treating physician discretion.
• Hematopoietic Stem Cell Transplantation (HCT) within 100 days of enrollment, or evidence of veno-occlusive disease (VOD) at any time post-transplant, or active acute graft-versus-host disease requiring systemic immunosuppressive therapy.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.
• Current systemic treatment with strong or moderate cytochrome P3A (CYP3A) inducers within seven days prior to enrollment.
• Any evidence of spontaneous tumor lysis syndrome (TLS).
• Active, significant, uncontrolled infection or severe infectious disease requiring therapy (bacterial, viral or fungal) as per the discretion of the treating physician.
• Presence of another active malignancy (requiring treatment) diagnosed within 12 months with the exception of:
  • adequately treated non-melanoma skin cancer;
  • adequately treated melanoma grade 2 or less;
  • cervical intraepithelial neoplasia;
  • adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
  • basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  • adequately treated prostate cancer;
• Life-threatening illness with life expectancy < 6 months unrelated to cancer.
• Known HIV positive patients who do not meet the following criteria:
  • Cluster of differentiation (CD4) count > 350 cells/mm^3;
  • Undetectable viral load;
  • Maintained on modern therapeutic regimens utilizing non-cytochrome (CYP)-interactive agents;
  • No history of AIDS-defining opportunistic infections;
• Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection.
  • Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.  Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
• Known hepatic cirrhosis or severe pre-existing hepatic impairment.
• Known cardiopulmonary disease defined as:
  • Unstable angina;
  • Congestive heart failure [New York Heart Association (NYHA) Class III or IV];
  • Myocardial infarction (MI) within six months prior to enrollment (subjects who had ischemic heart disease such as a (ACS), MI, and/or revascularization greater than six months before screening and who are without cardiac symptoms may enroll);
  • Symptomatic cardiomyopathy;
  • Clinically significant pulmonary hypertension requiring pharmacologic therapy;
  • Clinically significant arrhythmia:
    • History of polymorphic ventricular fibrillation or torsade de pointes;
    • Permanent atrial fibrillation [a fib], defined as continuous a fib for ≥ 6 months;
    • Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the four weeks before screening;
    • Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker); or ablation and
    • Patients with paroxysmal a fib or < Gr 3 a fib for period of at least six months are permitted to enroll provided that their rate is controlled on a stable regimen.
• Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study.
• Treatment with any investigational products, other than the study drugs, within 14 days before the study enrollment or during the study period.
• Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg).
• Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated as per institutional guidelines.
• Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography.
• Patients with uncontrolled coagulopathy or bleeding disorder.
• Known moderate-to-severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis.
• Major surgery within 14 days before the enrollment or a scheduled major surgery during study period.
• Known central nervous system (CNS) involvement with AML.
• Gastrointestinal (GI) tract disease that causes an inability to take oral medications, malabsorption syndrome, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis).
• Female subjects who are both lactating and breastfeeding or of childbearing potential who have a positive serum test during screening.
• Female subjects who intend to donate eggs (ova) during the course of this study or four months after receiving their last dose of study drug(s).
• Male subjects who intend to donate sperm during the course of this study or four months after receiving their last dose of study drug(s).
• Has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or star fruit from the day of consent to throughout the study period.

• Women aged 35 and older.
• Have had a negative routine mammogram within the last 12 months.
• Meets criteria for  intermediate breast cancer risk based on PRS score.

Exclusion Criteria:

• Known breast cancer at time of study or within 12 months of enrollment.
• Pregnant or lactating.
• Contraindication to intravenous iodinated contrast.
• Unable to understand or sign informed consent.
• Self-reported signs or symptoms of breast cancer.

Inclusion Criteria:

• Female.
• ≥ 18 years of age.
• English or Spanish speaking.
• Personal history of a phyllodes tumor.

• Male.
• Less than 18 years of age.
• Non-English or Spanish proficiency.
• History of prior Invitae 84-gene, multigene panel testing.

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