Eligibility last updated 3/31/22. Questions regarding updates should be directed to the study team contact.

• Practicing physicians, nurses and allied health staff that participate in surgery process.   

• Physicians, Nurses and allied health staff that do not have time to participate in the study.

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

• Age ≥ 18 years of age.
• Renal biopsy read at Mayo Clinic confirming the diagnosis of PGNMID.
• Proteinuria ≥ 1000 mg over 24 hours.
• Creatinine clearance ≥ 20 mL/min/SA.
• Subjects able and willing to give informed consent.
• For female subjects of reproductive childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 3 months after the last dose of any component of the treatment regimen. 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 drug. This birth control method must include one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings, or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy:
  • A woman of childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 10 to 14 days prior to dosing and the second within 24 hours prior to dosing;
  • A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 3 months after receiving the last dose of any component of the treatment regimen.
• For male subjects of reproductive potential who are sexually active with females ofreproductive potential must always use a latex or synthetic condom during the study and for 3 months after discontinuing study treatment (even after a successful vasectomy):
• • Male subjects of reproductive potential must not donate sperm during the study or for 3 months after the last dose of study treatment;
  • Must sign an informed consent form (ICF) or their legally acceptable representative must sign indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

• Pregnant or planning to become pregnant.
• Seropositive for human immunodeficiency virus (HIV).
• Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) will also be excluded. Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR and can be included.
• Multiple myeloma defined as >10% plasma cells on bone marrow biopsy and M-spike > 3 g/dL and presence of myeloma defining event (hypercalcemia, cast nephropathy, bone disease, or anemia), or plasma cells >60% or FLC ratio of involved to uninvolved > 100.
• Abnormal clinical labs defined as: anemia with Hgb < 8.0 g/dL, thrombocytopenia with platelet count < 75,000, leukopenia with WBC < 3.5, or neutropenia with ANC < 1000 , AST/ALT > 2.5 X ULN, bilirubin > 2 X ULN.
• Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal.
• Moderate or severe persistent asthma withing the past 2 years or uncontrolled asthma of any classification. Note the participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
• Clinically significant cardiac disease including:
  • Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to cardiac dysfunction (e.g. unstable angina, congestive heart failure, New York Heart Association Class III-IV);
  • Uncontrolled arrythmia.
• Prior or current exposure to any of the following:
  • To daratumumab or other anti-CD-38 therapies (unless a re-treatment study);
  • Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer;
  • Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication
•  Unable to provide consent.
• Patients receiving therapy with oral prednisone or glucocorticoid equivalent in the last 4 weeks.  Patients treated with low dose oral prednisone or glucocorticoid are allowed to be included if they are taking the medication for conditions unrelated to PGNMID (e.g., asthma, gout) at a daily dose of 10mg or less.
• Patients who had received immunosuppressive therapy with MMF, cyclosporine, tacrolimus, or azathioprine in the last 3 months.
• Patients who have received cyclophosphamide or bortezomib will be allowed to participate as long as there is clear evidence of lack of response to cyclophosphamide or bortezomib defined as lack of achieving complete or partial remission (see section 3.3 regarding definition).
• Patients who received rituximab previously with CD20 count of < 20 cells/microliter at the time of enrollment.
• Have received vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
• A history of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease before the date of randomization. Exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years.

Eligibility last updated 8/4/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 60 years old at time of consent.
• Concurrent enrollment in the Mayo Clinic Study of Aging (MCSA, IRB 14-004401):
  • Note: Participants may be but are not required to be concurrently enrolled in Brain Amyloid Imaging with Pittsburgh Compound B in Normal Aging, Mild Cognitive Impairment and Dementia (PiB, IRB 08-005553).  
•  Normal or mildly impaired cognition with CDR ≤ 1.0.

• History of dementia or major neurological condition (i.e., non-lacunar stroke, TBI, epilepsy, tumor, CNS infection, demyelinating disease, neurodegenerative disease), severe autonomic failure (pure autonomic failure or autonomic neuropathy), major psychiatric disease (i.e., alcohol/drug abuse and schizophrenia), 
• Current treatment of OSA. Diagnosed but untreated OSA is acceptable.
• Use of short-acting nitrates within 3 hours of the sleep study.
• Use of selective α1-adrenergic receptor antagonists, for example, tamsulosin (Flomax®), doxazosin (Cardura®), prazosin (Minipress®), and terazosin (Hytrin®) and nonselective α1 and α2 blockers (pentholamine and phenoxybenzamine).
• Finger deformity that precludes adequate sensor application.
• Placement of a permanent pacemaker.
• Persistent atrial fibrillation or other sustained non-sinus cardiac arrhythmias.
• Severe peripheral vascular disease (e.g., status post stent or by-pass surgery in one of the limbs, faint/absent pulses).
• Status post bilateral cervical or thoracic sympathectomy.
• Acute lung or heart disease (e.g., decompensated COPD or heart failure).

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

• Patient 18 years or older with breast cancer and biopsy-proven malignant involvement of an axillary lymph node.
• Surgical management will be determined by Dr. Mara Piltin, who will decide if preoperative I-125 seed localization of the positive node is necessary or if she will retrieve the positive node with intraoperative ultrasound guidance. During surgery, the targeted node, its associated biopsy markers, I-125 seed if placed, and twinkling marker will be resected. The position of the marker in the lymph node or proximity to the node will be noted from the surgical and pathology documentation.
• Surgery will be performed by Dr. Mara Piltin.
• Patients must be able to understand the study procedures and comply with them for the entire length of the study.
• No contraception is necessary or required.

• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Current or past participation within a specified timeframe in another clinical trial, as warranted by the administration of this intervention.

• Individuals ≥ 18 years of age.
• Clinicians and interpreters with experience in engaging with patients with Limited English Proficienct (LEP) and complex care medical needs.

• Individuals < 18 years of age.
• Those without experience engaging with patients with LEP and complex care medical needs.

Eligibility last updated 3/18/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 10/24/22. Questions regarding updates should be directed to the study team contact.

Key

• Diagnosed with 1 of the following diagnoses according to the 2016 World Health Organization (WHO) classification for systemic mastocytosis (SM):
  • Indolent systemic mastocytosis (ISM);
  • Smoldering systemic  mastocytosis (SSM).
• Moderate-to-severe symptoms based on a disease-specific PRO and after establishing a stable regimen of at least 2 antimediator therapies over a 14-day eligibility period.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2.
• For patients receiving corticosteroids, the dose must be ≤ 10 mg/day of prednisone or
• equivalent.

Key

• Diagnosed with any of the following WHO SM classifications: bone marrow mastocytosis, advanced systemic  mastocytosis including SM with associated hematologic neoplasm, aggressive SM, mast cell leukemia; or mast cell sarcoma.
• Diagnosed with mastocytosis of the skin without systemic involvement.
• Received prior treatment with any targeted KIT inhibitor.
• Received prior cytoreductive therapy or investigational agent for < 14 days or 5 half-lives of the drug and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before starting screening assessments.
• Received radiotherapy or psoralen and ultraviolet A therapy <14 days before starting screening assessments
• Received any hematopoietic growth factor support  < 14 days before starting screening assessments.
• History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study.
• Need for treatment of corticosteroids at > 10 mg/day of prednisone or equivalent.

Eligibility last updated 3/2/23. Questions regarding updates should be directed to the study team contact.

Aim 1-3 Patient Participants

• Age ≥ 50 years old;
• Estimated length of stay ≥ 24 hours in ICU; and
• Are not admitted for acute alcohol intoxication, drug (prescribed or illicit) overdose or withdrawal.

Aim 3 Nurse Clinician Participants

• Age ≥ 18 years old;
• Employed by Mayo Clinic;
• Assigned to care for study patient for > 4 hours.

Aim 3 Care Partner Participants

• Age ≥ 18 years old;
• Proxy decision maker for patient participant;
• Willing to complete survey (verbal consent).

Aim 1-3 Patient Participants

• Admitted for acute alcohol intoxication, drug (prescribed or illicit) overdose or withdrawal;
• Admitted for acute neuronal injury;
• Unable to communicate with research team due to sensory deficits (aphasic, blind, deaf); or
• Language (does not speak English).

Aim 3 Nurse Clinician Participants

• Not assigned to study patient.

Aim 3 Care Partner Participants

• Did not visit patient in ICU during study period;
• Already listed above in previous protocol version, was not copied/mentioned here.

Eligibility last updated 12/1/22. Questions regarding updates should be directed to the study team contact.

• Healthy male or female participants.
• Between the ages of 18 and 89.
• Must have had experience as a pilot or passenger in an unpressurized general aviation aircraft at altitudes above 8,000 feet and have not experienced any serious adverse effects from this experience (such as serious vertigo, loss of consciousness, any cardiac or respiratory dysfunction, or any other illness requiring medical treatment). 
• Participants need to be able to complete cognitive tests.
• Must be fluent in English.

• Patients < 18 years of age or > 89 years of age.
• Pregnant women.
• Unable to read and speak English.
• History of Cardiac disease, Pulmonary disease, Cerebrovascular disease, Neurological disease, Vertigo, or Syncope.
• Any documented incidences of Serious Adverse effects from General Aviation.

• Patients who receive a Hepatic Artery Infusion Pump at Mayo Clinic Rochester for localized unresectable liver metastases from colorectal cancer.
• Age ≥ 18 years old.
• Written consent.

• Age < 18 years old.
• Absence of written consent.
• Systemic disease.
• Pregnancy.

• Male or female.
• Between > 18-80 years of age.
• Able and willing to give informed consent 
• Subjects with a suspected glioblastoma tumor on pre-operative brain imaging scans.
• Subjects that are scheduled, or will be scheduled within 4 weeks, for surgical resection or biopsy per standard clinical tumor care.
• Karnofsky Performance Score > 70.
• Able to communicate sensations during the Exablate BBBD procedure.

• Tumor originating from the deep midline, thalamus, midbrain, cerebellum or brainstem.
• Multifocal tumors.
• MRI or clinical findings of:
  • Active or chronic infection(s) or inflammatory processes;
  • Acute or chronic hemorrhages, specifically any lobar microbleeds, and no siderosis, amyloid angiopathy, or macro-hemorrhages;
  • Intracranial thrombosis, vascular malformation, cerebral aneurysm or vasculitis.
• MR non-compatible metallic implants in the skull or the brain or the presence of unknown MR unsafe devices.
• Significant cardiac disease or unstable hemodynamic status:
  • Documented myocardial infarction within six months of enrollment;
  • Unstable angina on medication;
  • Unstable or worsening congestive heart failure;
  • Left ventricular ejection fraction below the lower limit of normal;
  • History of a hemodynamically unstable cardiac arrhythmia;
  • Cardiac pacemaker;
  • History of hypersensitivity to Perflutren lipid microsphere or its components; e.g., polyethylene glycol.
• Uncontrolled hypertension (systolic > 180 and diastolic BP > 120 on medication).
• Unable to discontinue use of anti-coagulant/antiplatelet therapy as per local standard.
• History of a liver disease, bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or evidence of increased risk of bleeding.
• Abnormal coagulation profile (Platelets < 80,000), PT (> 14) or PTT (> 36), and INR > 1.3.
• Known cerebral or systemic vasculopathy.
• Significant depression and at potential risk of suicide.
• Known sensitivity/allergy to gadolinium or DEFINITY®.
•  Active seizures despite medication treatment (defined as > 1 seizure per week) which could be worsened by disruption of the blood brain barrier.
• Active drug or alcohol disorder which have a higher risk for seizures, infection and/or poor executive functioning.
• Positive HIV status, which can lead to increased entry of HIV into the brain parenchyma leading to HIV encephalitis.
• Potential blood-borne infections which can lead to increased entry to brain parenchyma leading to meningitis or brain abscess.
• Any contraindications to MRI scanning, including:
  • Large subjects not fitting comfortably into the scanner;
  • Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia.
• Impaired renal function with estimated glomerular filtration rate < 30 mL/min/1.73m^2.
• Severe Respiratory Illness: chronic pulmonary disorders; e.g.,severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, subjects with a history of severe drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product labeling for Definity®.
• Currently in a clinical trial involving an investigational product or non-approved use of a drug or device.
• Pregnancy or lactation.

• 18 years or older with a clinician diagnosis of bipolar disorder (any bipolar disorder type including bipolar I disorder, bipolar II disorder, cyclothymic disorder, and unspecified bipolar and related disorder).
• Ability to consent to participation in research. 
• Patients (n=10) will be recruited from those currently receiving treatment in the included clinics in the Mayo Clinic (Collaborating Institution). 
• Additionally, stakeholder partners at the Depression and Bipolar Support Alliance will publicize our research study and identify 10-15 individuals with bipolar disorder currently receiving treatment to participate.

• Among participants recruited from the Mayo Clinic, individuals who are not intending to return to care in that system.
• No exclusion criteria apply to participants recruited from the Depression and Bipolar Support Alliance.

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

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

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

Eligibility last updated 10/6/22. Questions regarding updates should be directed to the study team contact.

• Patients who provide informed consent to participate in the study.
• Subjects: 18 years and older.
• Scheduled to undergo surgery resulting in a complex recovery as evaluated by the treating Department of Surgery surgeon.  This includes, but is not limited to, the following inpatient elective surgery procedures:
  • esophagectomy;
  • pancreatectomy;
  • pancreatectomy;
  • major liver resections;
  • open vascular surgery.
• Subjects are committed to daily exercise as outlined in the protocol.

• < 18 years of age.
• Subject is pregnant.
• Subject is dismissed from the hospital to a nursing home or long term care facility.
• Subject cannot commitment to daily exercise as outlined in the protocol.
• Subjects enrolled in another device or drug study does not necessarily preclude them from participating in this study.  Please check with the PI for inclusion if the subject is on another device or drug study.
• Subject does not have wifi access at home.
• Subject does not have a smartphone in which they can download the app for the watch device data to be downloaded.

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

Registration
•Inclusion Criteria

• Age ≥ 18 years
• Women with a diagnosis of breast cancer who are being treated with curative intent, with the one exception being women who are receiving CDK4/6 inhibitors (these patients being allowed to have more advanced disease).
• Provide written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Filling into one of the 5 groups discussed in section 5.0 (understanding that groups will close once they complete their accrual goals of 30 patients.
• Willingness to complete questionnaires every 3 months.
• Ability to complete the first questionnaire within 2 weeks of therapy initiation (for the four arms that are receiving adjuvant hormonal therapy).

Registration
•Exclusion Criteria

• Verbal baseline alopecia ≥ 2 on an 11 point scale (from none=0 to severe=10).   The question to use for this item is: Please rate your hair thinning or loss on a scale from 0 to 10, with 0 being no hair loss and 10 being complete hair loss.
• Planned receipt of chemotherapy or another cancer-directed therapy concurrently (e.g., everolimus, etc.; note that a CDK4/6 inhibitor is allowed within cohort 3).
• Prior use of endocrine therapy for breast cancer.
• Receipt of chemotherapy over the previous 6 months.

Eligibility last updated 7/18/22. Questions regarding updates should be directed to the study team contact.

Registration
•Inclusion Criteria

• Age ≥ 18 years
• Women with a diagnosis of breast cancer who are being treated with curative intent, with the one exception being women who are receiving CDK4/6 inhibitors (these patients being allowed to have more advanced disease).
• Provide written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Filling into one of the 5 groups discussed in section 5.0 (understanding that groups will close once they complete their accrual goals of 30 patients.
• Willingness to complete questionnaires every 3 months.
• Ability to complete the first questionnaire within 2 weeks of therapy initiation (for the four arms that are receiving adjuvant hormonal therapy).

Registration
•Exclusion Criteria

• Verbal baseline alopecia ≥ 2 on an 11 point scale (from none=0 to severe=10).   The question to use for this item is: Please rate your hair thinning or loss on a scale from 0 to 10, with 0 being no hair loss and 10 being complete hair loss.
• Planned receipt of chemotherapy or another cancer-directed therapy concurrently (e.g., everolimus, etc.; note that a CDK4/6 inhibitor is allowed within cohort 3).
• Prior use of endocrine therapy for breast cancer.
• Receipt of chemotherapy over the previous 6 months.

Eligibility last updated 7/18/22. Questions regarding updates should be directed to the study team contact.

Registration
•Inclusion Criteria

• Age ≥ 18 years
• Women with a diagnosis of breast cancer who are being treated with curative intent, with the one exception being women who are receiving CDK4/6 inhibitors (these patients being allowed to have more advanced disease).
• Provide written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Filling into one of the 5 groups discussed in section 5.0 (understanding that groups will close once they complete their accrual goals of 30 patients.
• Willingness to complete questionnaires every 3 months.
• Ability to complete the first questionnaire within 2 weeks of therapy initiation (for the four arms that are receiving adjuvant hormonal therapy).

Registration
•Exclusion Criteria

• Verbal baseline alopecia ≥ 2 on an 11 point scale (from none=0 to severe=10).   The question to use for this item is: Please rate your hair thinning or loss on a scale from 0 to 10, with 0 being no hair loss and 10 being complete hair loss.
• Planned receipt of chemotherapy or another cancer-directed therapy concurrently (e.g., everolimus, etc.; note that a CDK4/6 inhibitor is allowed within cohort 3).
• Prior use of endocrine therapy for breast cancer.
• Receipt of chemotherapy over the previous 6 months.

Eligibility last updated 7/18/22. Questions regarding updates should be directed to the study team contact.

• Adult male and female, age from 18 years old.
• Having signs and symptoms of HFpEF. HFpEF (EF ≥ 40%, PCWP at rest ≥15 mm Hg).
• With 1, 2, 3 grades or indeterminate degree of DD (ACC/AHA stages C and D HF).

• Reduced Ejection Fraction (EF ≤ 39%), mitral valve prosthesis, mitral stenosis.

Eligibility last updated 9/16/22. Questions regarding updates should be directed to the study team contact.

• Scheduled for a MR guided biopsy or ablation.
• Male, 45 years of age or older.
• One, two, or three tumor suspicious regions identified on multiparametric MRI.
• Tolerance for anesthesia/sedation.
• Ability to give informed consent.

• Presence of any condition (e.g., metal implant, shrapnel) not compatible with MRI.
• History of other primary non-skin malignancy within previous three years.

• Adult patients ≥ 18 years old.
• Diagnosed with plasma cell disorders.

• Children < 18 years old.
• Pregnant females.

Eligibility last updated 5/2/22. Questions regarding updates should be directed to the study team contact.

Part A Main

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

Eligibility last updated 1/19/23. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 9/23/22. Questions regarding updates should be directed to the study team contact.

• Children diagnosed with autism spectrum disorder (ASD).
• Between 2 years, 0 months to 4 years, 11 months of age.
• With less than phrased speech.
• Child must have at least one caregiver willing to participate in the study.

• Children and parents if they do not meet the above inclusion criteria.

   

• Subject (or legal guardian where applicable) is willing and able to provide signed informed consent (or assent when applicable) and can follow protocol requirements.
• Have histologically- or cytologically-confirmed disease, which is relapsed/ refractory, and unresectable or metastatic disease, following at least 1 prior line of standard-of-care systemic therapy (systemic therapy may be administered with or without the use of surgery or radiation) and must not be candidates for therapies available that are known to confer clinical benefit:
  • Synovial sarcoma;
  • A SMARCB1-null tumor as determined by immunohistochemistry, fluorescent in situ hybridization, or other equivalent tests like gene mutation analysis.
• ≥ 18 years of age or ≥ 16 years old and weighs ≥ 50 kg:
  • Adolescent enrichment cohort: 16 to 17 years of age and weighs ≥ 40 kg.
• Subject able to safely swallow tablet or pill.
• Measurable disease as defined by RECIST v1.1, a lesion which is ≥ 10 mm in the longest diameter by computed tomography scan or ≥ 10 mm measurable by calipers on physical examination.
• Eastern Cooperative Oncology Group performance status ≤ 2:
  • Adolescent enrichment cohort: Lansky performance scale (LK scale): ≥ 60.
• Adequate organ function, defined as:
  • Bone marrow function: absolute neutrophil count ≥ 1.0 x 10^9 /L independent of growth factor support for ≤ 7 days prior to first dose of study drug for granulocyte colony-stimulating factor and ≤ 14 days prior to first dose of study drug for pegfilgrastim; hemoglobin ≥ 8 g/dL independent of transfusion support for ≤ 7 days prior to first dose of study drug; platelet count ≥ 75 x 10^9 /L independent of transfusion support for ≤ 3 days prior to first dose of study drug;
  • Coagulation: Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x the upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) < 1.5 x ULN (unless the subject is receiving anticoagulant therapy and INR and partial PT/aPTT are within therapeutic range of intended use of anticoagulants);
  • Liver function: total bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN for subjects with Gilbert’s syndrome), aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN; except for subjects who have tumor infiltration of the liver, where ALT and AST ≤ 5 x ULN;
  • Renal function: must have a creatinine clearance ≥ 60 mL/min (CockcroftGault equation);
  • Cardiac function: baseline corrected QT interval using Fredericia’s formula ≤ 470 ms (adolescents 12-17 years of age: ≤ 450 ms) and a left ventricular ejection fraction ≥ 50% evaluated via echocardiogram.
• Have available archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor not previously irradiated.
• A female subject may be eligible to participate if she is not pregnant or planning a pregnancy, not breastfeeding, and at least 1 of the following conditions applies:
  • A woman of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone > 40 MIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] must be obtained);
  • Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1 of the contraception methods specified if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment.;
  • For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw, with the exact interval dependent on the type and dosage of HRT. Following confirmation of their postmenopausal status, the subject can resume use of HRT during the study without use of a contraceptive method;
  • A woman of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 30 days for females after the last dose of study treatment, must:
    • Have 2 negative pregnancy tests verified by the investigator prior to the first dose of CFT8634;
    • Have serum pregnancy test within 14 days prior to Cycle 1 Day 1;
    • Urine pregnancy test within 24 hours prior to first dose;
    • Agree to having ongoing pregnancy tests during the study and after discontinuation of the study.
  • Highly effective contraception methods include:
    • Female sterilization, total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment;
    • For male partners of female subjects: Male sterilization (at least 6 months prior to screening);
    • Use of 2 reliable forms of contraception without interruption at least 30 days prior to first dose, during the conduct of the study including periods of dose interruptions of the study treatment, and for 30 days for females after discontinuation of CFT8634.
• A male subject must have either had a prior vasectomy or agree to use a condom during the treatment period and for at least 90 days after the last dose of study treatment.
• Males must refrain from donating sperm while taking CFT8634 and for 90 days after discontinuation.
• Females must refrain from donating ova while taking CFT8634 and for 30 days after discontinuation.
• Subjects must refrain from donating blood during study treatment and for 30 days after discontinuation.

• Has received major surgery within 3 weeks prior to the planned first dose of CFT8634:
  • Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
• Has received standard of care or investigational systemic anti-neoplastic therapy within 14 days or 5 half-lives, whichever is shorter, prior to the planned first dose of CFT8634.
• Has received radiation therapy within 14 days prior to the planned first dose of CFT8634.
• Prior treatment with a BRD9 degrader, unless approved following discussion with the Sponsor.
• Subjects with central nervous system (CNS) involvement (primary tumor or metastatic disease), except in the following circumstances:
  • Subjects with previously treated brain metastases may be permitted to participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study treatment and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and, if they are taking corticosteroids, they are on stable or tapering doses for at least 7 days prior to first dose of study treatment. Antiseizure therapy is permitted provided the medication is not otherwise excluded and seizures have been controlled for at least 4 weeks since the last antiseizure medication adjustment;
  • Subjects with asymptomatic brain metastases found on screening magnetic resonance imaging (MRI) may be permitted to be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.
• Subject has any evidence of a CNS bleed including intratumoral hemorrhage.
• Known bleeding diathesis.
• Impaired cardiac function or clinically significant cardiac disease including any of the following:
  • Congestive heart failure requiring treatment, with at least a New York Heart Association Class II;
  • Uncontrolled arterial hypertension;
  • Clinically significant arrythmias (subjects well-controlled on medication may be considered eligible following discussion and documented approval of the Sponsor) d. Unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of study treatment.
• Presence of inflammatory vascular disease or microangiopathy (e.g., thrombotic microangiopathies, hemolytic uremic syndrome [HUS], atypical HUS).
• Known malignancy, other than study indication, that is progressing or has required treatment within the past 3 years.
  • Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Received live, attenuated vaccine within 4 weeks of first dose of study treatment.
• Known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
• Subjects with a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or at risk for HBV/HCV infection must have a negative HBV/HCV test to be considered eligible for this study.
• Had a venous thrombosis within 2 weeks prior to first dose of study drug.
  • Note: Subjects with a history of a deep vein thrombosis > 2 weeks prior to the first dose of study drug who are stable on anticoagulation therapy may be eligible for this study.
• Uncontrolled active systemic infection or any life-threatening illness, medical condition, or organ system dysfunction that could compromise the subject’s safety or put the study outcomes at undue risk.
• Subjects with gastrointestinal absorption issues (e.g., malabsorption syndrome or other illness that could affect oral absorption).
• Concurrent administration of strong cytochrome P450 (CYP) 3A4 inhibitors and inducers, and multidrug resistance mutation 1 inhibitors.
  • Note: If a subject can be switched to a similar agent that is not a strong CYP3A modulator or is a weak CYP3A modulator they may be permitted to enroll in the study.
• Proton pump inhibitor (PPI) drugs must be discontinued at least 7 days prior to the first dose of study drug and H2 blockers should be discontinued at least 24 hours prior to the start of study drug. Other antacid medication, like calcium containing medications, may be administered at least 6 hours from study treatment.
• Presence of grade > 2 toxicity (Common Terminology Criteria for Adverse Events v5.0) due to prior cancer therapy (subjects with alopecia may be enrolled).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound results of the study, interfere with the subject’s participation for full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has a known psychiatric or substance abuse disorder that would interfere with cooperating with requirements of the study.
• Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 30 days (female) or 90 days (male) after the last dose of study treatment/discontinuation.
• Previously identified hypersensitivity to components of the study treatment or excipients.

Eligibility last updated 6//28/22. Questions regarding updates should be directed to the study team contact.

• Biopsy confirmed Grade 1-2 endometrioid endometrial cancer or complex atypical hyperplasia.
• No major surgery within 3 months of diagnosis.
• Diagnosis in the last 10 years.
• BMI ≥ 40 kg/m^2.
• English speaking.

• Non-English speaking.
• Advanced stage endometrial cancer or histology other than endometrioid.

Eligibility last updated 5/13/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria (Part A):

- Clinical or mutational diagnosis of TSC

- Failure to control seizures despite appropriate trial of 2 or more ASMs at therapeutic
doses.

- Have at least 8 countable/witnessed primary seizures during the 4-week baseline period
with at least 1 primary seizure occurring in at least 3 of the 4 weeks of baseline.

Inclusion Criteria (Part B)

? Patients have experienced ≥ 35% reduction in primary seizure frequency during the Part A
treatment period compared to the 4-week Baseline Period.

Exclusion Criteria (Part A):

- Previous exposure to GNX

- Pregnant or breastfeeding

- Concurrent use of strong inducers or inhibitors of cytochrome P450 (CYP)3A4/5/7. Any
strong inhibitor or inducer of CYP3A4/5/7 must be discontinued at least 28 days before
Visit 2, study drug initiation. This does not include approved ASMs.

- Patients who have been taking felbamate for less than 1 year prior to screening

- Patients who test positive for tetrahydrocannabinol (THC) or non-approved cannabidiol
(CBD) via plasma drug screen

- Chronic use of oral steroid medications, ketoconazole (except for topical
formulations), St. John's Wort, or other IPs is not permitted

- Have an active CNS infection, demyelinating disease, degenerative neurological
disease, or CNS disease deemed progressive. This includes tumor growth which in the
opinion of the investigator could affect primary seizure control

- Patients with significant renal insufficiency, estimated glomerular filtration rate
(eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR
calculator or Bedside Schwartz), will be excluded from study entry or will be
discontinued if the criterion is met post baseline

- Have been exposed to any other investigational drug within 30 days or fewer than 5
half lives (whichever is shorter) prior to the screening visit

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

Eligibility last updated 5/10/23. Questions regarding updates should be directed to the study team contact.