• Patients referred to the Mayo Clinic HF Clinic with a diagnosis of heart failure who have a clinical blood draw scheduled.
• Adults ≥ 18 years old.

• Individuals < 18 years old.
• Any history of Hemoglobin less than 9 mg/dL during the past 3 months.
• Active cancer.

Eligibility last updated 1/28/22. Questions regarding updates should be directed to the study team contact.

• Esophageal cancer any stage.
• Age ≥ 18 years old.
• Willing and able to provide consent.
• No prior history of neoadjuvant therapy for the esophageal cancer.

• Age < 18 years old.
• Unable to provide consent.

Eligibility last updated 2/11/22. Questions regarding updates should be directed to the study team contact.

• Adult males and females over the age of 18.
• Subjects living at Acacia Creek Retirement Community who use a Sleep Number® bed.

• Individuals under the age of 18.
• Subjects who do not have a Sleep Number® bed.
• Subjects without an internet connection to transmit nightly SleepIQ® data.

Eligibility last updated 1/31/22. Questions regarding updates should be directed to the study team contact.

Subjects must satisfy all following criteria at the Screening visit unless otherwise stated:

• Male or female aged 18 years or older.
• Able to provide written informed consent.
• Active and consistent cortisol excess:
  • Active and consistent cortisol excess: This is defined as UFC > upper limit of normal (ULN) based on at least 2 valid (i.e., complete) 24-hour urine samples collected during Screening. The subjects will be provided collection devices for three 24-hour collections to ensure 2 complete collections are received, particularly if a subject requires washout of other cortisol-suppressing agents. If more than 2 valid collections are received; the mean of all valid completed collections collected after completion of the washout period (if applicable), and available at Day 1 must be >ULN, as confirmed by the central laboratory. Should an additional, otherwise disqualifying, UFC value become available only after Day 1 randomization, the subject will be allowed to continue planned treatment and a sensitivity, per-protocol analysis will be conducted.
• Documented diagnosis of ACTH-dependent Cushing’s syndrome:
• This includes Cushing’s disease, ectopic ACTH secretion, and ectopic CRH secretion. Subjects may include newly diagnosed patients who have declined or are not considered candidates for surgery or patients with residual or recurrent disease after surgery in whom surgery or radiation are not planned within the next 6 months. Previous medical records will be used to support the diagnosis.
• At least 1 of the following will be considered satisfactory to establish the diagnosis:
• History of positive ACTH-staining pathology.
• History of documented, transient, AI after tumor removal requiring glucocorticoid replacement.
• ACTH level > 20 pg/mL with positive ACTH or cortisol response to CRH or desmopressin (DDAVP) stimulation in the presence of hypercortisolemia.
• Inferior petrosal sinus sampling with ACTH central:plasma gradient ≥ 2 before CRH or DDAVP or ≥ 3 after CRH or DDAVP.
• Presumptive Cushing’s disease based on presence of a pituitary tumor ≥ 6 mm along with positive ACTH or cortisol response to CRH or DDAVP stimulation or an overnight or high-dose (8 mg) dexamethasone suppression of cortisol, performed and interpreted according to locally recognized standards of diagnosis.
• In the absence of any of the above, an individual might be eligible if ectopic ACTH-dependent Cushing’s syndrome was otherwise confirmed via adequate testing consistent with the local standards of care. Such cases must be discussed with and explicitly approved by the Medical Monitor and Sponsor, and the specific diagnostic criteria used to establish the diagnosis of ACTH-dependent Cushing’s syndrome must be documented.
• Willing to comply with reproductive precautions.
• Current evidence of Cushing’s morbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia:
  • Defined by having at least 1 of the below criteria, ideally including both or either of “a” and “b”, but including any of “a”, “b”, “c”, or “d”.
    • Diagnosis of insulin-resistance/pre-diabetes or type 2 diabetes: Including subjects on stable diabetic treatment, but excluding those ethically requiring further or frequent therapy adjustments. Type 2 diabetes is defined as a current HbA1c ≥ 6.5% but ≤ 9.5% (otherwise excluded), fasting blood glucose (FBG) > 126 mg/dL, or 2 hr OGTT ≥ 200 mg/dL. Pre-diabetes is defined as current HbA1c < 6.5 but > 5.7%, FBG > 100 to 125 mg/dL, or 2-hour OGTT 140 to 199 mg/dL. Insulin-resistance may also be defined by abnormal HOMA-IR > 2.5 or by CGM data (e.g., mean glucose, glycemic variability, time in range, estimated HbA1c)28;
    • Diagnosis of dyslipidemia: This is evidenced by history of total cholesterol level of ≥ 6.2 mmol/L (240 mg/dL) or triglycerides of ≥ 5.2 mmol/L (200 mg/dL) Current total cholesterol may be < 6.2 mmol/L, and current triglycerides may be < 5.2 mmol/L, if controlled with allowed lipid-lowering therapy;
    • Diagnosis of hypertension: Incident hypertension should be brought under control and stabilized prior to randomization at Day 1. Subjects with hypertension which is reasonably, but sub-optimally managed by standard therapy at baseline (systolic blood pressure [SBP] >140 but < 180 or DBP > 90 but < 120 mmHg) qualify;
    • Diagnosis of osteoporosis or osteopenia: Osteopenia (T-score ≤ -1.0 or Z-score ≤ -2.0) or osteoporosis as determined previously, during by the site’s local Baseline DEXA reading, or history or evidence of minimal-traumatic or osteoporotic fracture treated with lifestyle modification with mineral or vitamin supplementation or stable approved osteoporosis therapies.

Exclusion Criteria

Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit unless otherwise stated:

• Recent or planned Cushing’s surgery: Surgery for Cushing’s within the past 6 weeks or planned within 24 weeks after randomization.
• Use of medications for Cushing’s syndrome within the washout periods prior to randomization.
• Recent Cushing’s radiotherapy: Any fractionated radiation therapy for Cushing’s within the past 2 years, or conventional radiation therapy within 4 years.
• History of bilateral adrenalectomy.
• History of pseudo-Cushing’s syndrome.
• History of cyclic Cushing’s syndrome.
• Exogenous hypercortisolism or factitious Cushing’s syndrome.
• History of non-ACTH-dependent hypercortisolism:
• This includes that caused by a known inherited syndrome (e.g., McCune Albright syndrome, Carney complex) but not including multiple endocrine neoplasia type 1 where diagnostic testing has led to a diagnosis of Cushing’s disease (79%) while excluding autonomous adrenal Cushing’s syndrome (21%).
• High risk of Nelson’s syndrome: Current evidence of macroadenoma with, or at risk of, optic nerve or vital structure compression, e.g., tumor showing aggressive growth within 2 mm of optic chiasm or with evidence of blood-vessel encroachment.
• Uncontrolled Cushing’s morbidities of hyperglycemia, dyslipidemia, hypertension, or osteopenia:
• Including evidence of chronic, poor glycemic control (HbA1c > 9.5%), symptomatic dyslipidemia (e.g., hypercholesterolemia with recent (< 1 year) cerebro- or cardiovascular events, hypertriglyceridemia with pancreatitis), persistent uncontrolled hypertension (systolic blood pressure > 180 mmHg or DBP > 120 mmHg), or recent (< 1 year) osteoporotic fracture ethically requiring additional medical intervention.
• Use of drugs likely to interfere with study assessments:
• These include chronic systemic corticosteroids, thiazolidinediones, 5-alpha-reductase inhibitors, certain drugs that affect cognitive testing (e.g., oxybutynin or opioids) within 12 weeks prior to the first dose of study drug. See concomitant medications section for recommendations regarding use of certain other allowed medications.
• Uncontrolled hypothyroidism or hyperthyroidism: Free thyroxine should be in normal range and stable, whether endogenous or on levothyroxine replacement [> 8 weeks] and without elevated thyroid-stimulating hormone.
• Moderate or severe renal impairment: Defined by an estimated glomerular filtration rate (GFR) repeatedly < 60 mL/min or confirmed by measured GFR < 60 mL/min.
• Medically significant liver disease.
• Including cirrhosis, chronic active hepatitis, chronic persistent hepatitis, or subjects with serum total bilirubin > 1.5 × ULN (unless previously diagnosed with benign Gilbert’s disease) or serum ALT or AST >3 × ULN.
• Medically significant cardiovascular or ECG abnormalities:
• This includes patients with recent (< 1 year) myocardial infarction or stroke, orthostatic or vasovagal syncope, QT interval corrected (QTc) intervals > 500 ms, or evidence of significant, life-threatening arrhythmia or bradycardia (HR < 45 bpm).
• History of idiopathic thrombocytopenic purpura.
• History of adrenal carcinoma.
• Recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: Positive test for infection within the past 4 weeks or hospitalization for coronavirus disease 2019 (COVID-19) within the past 6 months.
• History of cancer within 3 years other than ectopic ACTH from an unidentified source, non-melanoma skin cancer, thyroid cancer, or early-stage prostate cancer.
• If stable and requiring hormone-suppressive therapy, patients with prostate cancer may be included at Medical Monitor discretion, however their data may be excluded in assessment of SPI-62 effects on HPA and HPG axes).
• Any major surgery, or significant post-operative sequelae, within 1 month prior to informed consent or planned during the trial.
• Pregnant, lactating, or planning fertility in the next 6 months and unwilling to adhere to approved contraceptive use or abstinence.
• Participation in any clinical trial within 1 month prior to informed consent (or longer for biologic and long-lasting experimental therapies).
• Receipt of blood products within 2 months prior to Screening.
• Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Subjects are not to donate blood, plasma, or platelets during the study.
• Poor peripheral venous access.
• Any other current or prior medical condition expected to interfere with the conduct of the study or the evaluation of its results.

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 12/21/22]. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 7/27/22. Questions regarding updates should be directed to the study team contact

• Male patients.
• Age 45-80 years, with > 10 years life expectancy.
• Biopsy-confirmed, NCCN (favorable GG2 and unfavorable GG3) intermediate-risk prostate cancer.
• Stage ≤ T2c, N0, M0.
• ISUP Grade Group 2 or 3 disease on TRUS-guided biopsy (minimum 8 cores, combination of systematic and MRI fusion-guided) or in-bore biopsy (minimum 3 cores from each PI-RADS v2 category ≥ 3 lesion). Biopsy reported within 12 months of baseline visit, with minimum 6-week interval between biopsy and baseline.
• PSA ≤ 20 ng/mL reported within 3 months of baseline.
• Treatment naïve.
• Planned ablation volume < 3.0 cm axial radius from the urethra on mpMRI acquired within 6 months of baseline.  

• Inability to undergo MRI or general anaesthesia.
• Suspected tumour > 30 mm from the prostatic urethra.
• Prostate calcifications > 3 mm in maximum extent obstructing ablation of tumour on low-dose pelvic CT:                
  • Criteria subject to additional review and approval by sponsor. Alternatively, prospective TRUS to query calcifications or susceptibility-weighted MRI if available may be used to assess calcifications. Imaging for calcification screening must be dated within 1 year of baseline visit.
• Unresolved urinary tract infection or prostatitis.
• History of proctitis, bladder stones, hematuria, history of acute urinary retention, severe neurogenic bladder.
• Artificial urinary sphincter, penile implant or intraprostatic implant.
• Less than 10 years life expectancy.
• Patients who are otherwise not deemed candidates for RP.
• Inability or unwillingness to provide informed consent.
• History of anal or rectal fibrosis or stenosis, or urethral stenosis, or other abnormality challenging insertion of devices.

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

• Male and female patients aged ≥ 18 years at the time of informed consent form (ICF) signature.
• Received allogeneic HSCT from a related or unrelated, human leukocyte antigen-matched or mismatched donor. Patients having received any of the following stem cell sources are eligible: granulocyte colony stimulating factor mobilized peripheral blood stem cells, bone marrow, umbilical cord blood.
• Diagnosis of TA-TMA established by histologic evidence of microangiopathy in any biopsied organ OR, as per the laboratory markers below, indicating TMA:
  • De novo or progressing thrombocytopenia (platelet count < 50 x 10^9/L or > 50 % decrease in platelet count from the highest value achieved after transplantation); AND
  • Elevated LDH (> 1.5 x ULN); AND
  • At least 1 additional laboratory criteria among the following:
  • Schistocytes on the peripheral blood smear (≥ 2 per hpf); OR
  • De novo anemia (hemoglobin < LLN or anemia requiring PRBC transfusion support as per local institutional standard); OR
  • Proteinuria (rUPCR ≥ 2 mg/mg); OR
  • Elevated plasma concentration of sC5b-9 above ULN.
• Have a diagnosis of TA-TMA that persists despite initial management of any triggering condition.
• Have at least 1 sign/symptom of organ dysfunction:
  • Kidney: doubling of serum creatinine compared with pre-HSCT level or patient receiving renal replacement therapy or proteinuria ≥ 30 mg/dL AND rUPCR ≥ 2 mg/mg;
  • Lungs: hypoxemia or any need for noninvasive or invasive positive pressure ventilation;
  • Cardiovascular: pulmonary hypertension diagnosed by a cardiologist using cardiac catheterization, or pulmonary hypertension criteria on echocardiography or arterial hypertension, defined by systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg at baseline or hypertension requiring > 2 medications (excluding diuretics);
  • Serositis: clinically significant pleural effusion or pericardial effusion requiring surgical therapy (e.g., pericardiocentesis/ thoracocentesis);
  • CNS: seizures attributable to posterior reversible encephalopathy syndrome;
  • GI tract: presence of biopsy-proven GI TA-TMA. Patients with GI bleeding (hematemesis or hematochezia) will be excluded.
• Women of childbearing potential, defined as any women who have experienced menarche and who are NOT permanently sterile or postmenopausal, must have a negative serum pregnancy test at screening and agree to use protocol-defined methods of contraception for the duration of the study and 8 weeks after their last IMP dose.
  • Note: Postmenopausal is defined as having had 12 consecutive months with no menses without an alternative medical cause.
• Men must agree to the following for the duration of the study and 8 weeks after their last dose of IMP:
  • Avoid fathering a child;
  • Use protocol-defined methods of contraception;
  • Refrain from donating sperm.
• Patient and/or legally authorized representative must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF.

• Positive direct Coombs test.
• Known familial or acquired ADAMTS13 deficiency.
• Known Shiga toxin‐related hemolytic uremic syndrome.
• Known bone marrow or graft failure.
• Diagnosis of disseminated intravascular coagulation.
• Diagnosis of VOD.
• Active GI bleeding (hematemesis or hematochezia) at baseline.
• Body weight < 30 kg and > 100 kg.
• Uncontrolled systemic bacterial or fungal infection, presence or suspicion of sepsis.
• Previously or currently treated with a complement inhibitor (approved or investigational).
• Pregnancy or breastfeeding.
• Positive human immunodeficiency virus antibody at screening or documented in pre-HSCT medical record.
• Hepatitis C virus detectable by polymerase chain reaction at screening or documented in pre-HSCT medical record.
• Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at screening or documented in pre-HSCT medical record. Eligible patients who are chronic active carriers (≤ 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine) according to local country guidelines.
• Inability to cooperate with study procedures or any condition that, in the opinion of the investigator, could increase the patient’s risk by participating in the study or confound the outcome of the study.

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

• Women who will give birth at Mayo Clinic by caesarean-section at term following an uncomplicated pregnancy.

• Multiple pregnancy.
• Known presence of clinical infections (e.g., chorioamnionitis), congenital anomalies or maternal pathologies (i.e., diabetes, hypertension, preeclampsia).
• Intrauterine growth retardation or fetal macrosomia.
• Maternal age under 18 or over 50.
• Maternal body mass index (BMI) of less than 18 and more than 40.
• Pregnancy less than 37 weeks of completed gestation.

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

• Age 22
  •65 years.
• BMI ≥ 35 and < 40 kg/m^2 or BMI of 30 to 34.9 kg/m^2 with one or more major obesity-related comorbid conditions.
• Willingness to comply with the substantial lifelong dietary restrictions required by the procedure.
• History of obesity (BMI ≥ 30) for at least 2 years.
• History of failure with non-surgical weight loss methods.
• Willingness to follow protocol requirements, including signed informed consent, routine follow-up schedule, completing laboratory tests, completing diet counseling.
• Residing within a reasonable distance from the investigator’s office and able to travel to the investigator to complete all routine follow-up visits.
• Ability to give informed consent.
• Women of childbearing potential (i.e., not post-menopausal or surgically sterilized) must agree to use adequate birth control methods.  Acceptable birth control methods are limited to hormonal contraceptives (oral, flexible vaginal ring, skin patch, injection), diaphragms, IUDs, condoms with or without spermicide, and voluntary abstinence.  Should a treatment arm subject become pregnant during the implantation period, the balloon will be extracted during the second trimester
  •the timing of which will be determined via consultation with the subject’s obstetrician.

• Prior surgery involving the esophagus, stomach, and duodenum or bariatric surgery.
• Prior open or laparoscopic bariatric surgery.
• Prior surgery of any kind on the esophagus, stomach, duodenum or any type of hiatal hernia surgery.
• Any inflammatory disease of the gastrointestinal tract including esophagitis, Barrett’s esophagus, gastric ulceration, duodenal ulceration, cancer or specific inflammation such as Crohn’s disease
• Potential upper gastrointestinal bleeding conditions such as esophageal or gastric varices, congenital or acquired intestinal telangiectasis, or other congenital anomalies of the gastrointestinal tract such as atresias or stenoses.
• A gastric mass.
• A hiatal hernia > 2cm or severe or intractable gastro-esophageal reflux symptoms.
• Acid reflux symptoms to any degree that require more than one medication for symptom control.
• A structural abnormality in the esophagus or pharynx such as a stricture or diverticulum that could impede passage of the balloon alongside the endoscope.
• Achalasia or any other severe esophageal motility disorder that may pose a safety risk during the removal of the device.
• Severe coagulopathy.
• Insulin-dependent diabetes (either Type 1 or Type 2) or a significant likelihood of requiring insulin treatment in the following 12 months.
• Subjects with any serious health condition unrelated to their weight that would increase the risk of endoscopy.
• Chronic abdominal pain.
• Motility disorders of the GI tract such as gross esophageal motility disorders, gastroparesis or intractable constipation.
• Hepatic insufficiency or cirrhosis.
• Serious or uncontrolled psychiatric illness or disorder that could compromise patient understanding of or compliance with follow up visits and removal of the device after 8 months.
• Alcoholism or drug addiction.
• Patients unwilling to participate in an established medically-supervised diet and behavior modification program, with routine medical follow-up.
• Patients receiving daily prescribed treatment with aspirin, anti-inflammatory agents, anticoagulants or other gastric irritants.
• Patients who are unable or unwilling to take prescribed proton pump inhibitor medication for the duration of the device implant.
• Patients who are known to have, or suspected to have, an allergic reaction to materials contained in the system.
• Patients who have BOTH:
  • A previous history of a serotonin syndrome; AND
• • currently taking any drug known to affect the levels of serotonin in the body [e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs)].
• Patients who are pregnant or breast-feeding.
• Subjects with severe cardiopulmonary disease or other serious organic disease which might include known history of coronary artery disease, myocardial infarction within the past 6 months, poorly controlled hypertension, required use of NSAIDs.
• Subjects who have tested positive for H. Pylori, and who have not yet been treated.

Eligibility last updated 2/3/22. Questions regarding updates should be directed to the study team contact.

• Deceased children with partial ornithine transcarbamylase (OTC) deficiency who were under strict treatment and died unexpectedly, and their parents.

• Lack of quality or significant volume of DNA from all submitted specimens.

Eligibility last updated 2/3/22. Questions regarding updates should be directed to the study team contact.

• Informed consent/assent:
  • For adult participants (≥ 18 years of age), ability to comprehend and willingness to sign an ICF;
  • For adolescent participants (≥ 12 to < 18 years of age), written informed consent of the parent(s) or legal guardian and written assent from the adolescent participant.
    • Note: Adolescents who during the course of the study become legal adults will be asked for their consent to participate in the study.
• Female and male adults and adolescents ≥ 12 years of age.
• Clinical diagnosis of FOP (based on findings of congenital malformation of the great toes, episodic soft-tissue swelling, and/or progressive HO).
• Participant-reported FOP disease activity within 1 year of the screening visit. This is defined as pain, swelling, and other signs and symptoms associated with FOP flare-ups or wosening of joint function or radiographic progression of HO (increase in site or number of HO lesions) with or without an association with flare-up episodes.
• Ability to swallow and retain orally administered tablets, either whole or crushed and dispersed in foods or liquids.
• Willingness to avoid pregnancy or fathering children based on the criteria below.
  • Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days after the last dose of study drug and must refrain from donating sperm during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
  • Female participants of childbearing potential must have a negative pregnancy test at screening (serum) and before the first dose on Day 1 (urine). Female participants of childbearing potential must agree to take appropriate precautions to avoid pregnancy from screening through 190 days after the last dose of study drug and must refrain from donating oocytes during this period. Permitted methods in preventing pregnancy should be communicated to the participants and their understanding confirmed.
  • Women without childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible.
• Willing and able to undergo low-dose WBCT (excluding the head) imaging without requiring intubation.
• Willing and able to comply with study procedures and requirements and attend all study visits as defined in this Protocol.

• Pregnant or breast-feeding.
• CAJIS score ≥ 24.
• FOP disease severity that in the investigator's opinion precludes participation (e.g., ankyloses of most or all joints, symptomatic thoracic insufficiency syndrome, or recurrent respiratory infections).
• History of uncontrolled or unstable cardiovascular, respiratory, renal, gastrointestinal, endocrine, hematopoietic, psychiatric, and/or neurological disease within 6 months of screening.
• Any clinically significant medical condition other than FOP that would, in the investigator's judgment, interfere with full participation in the study, pose a significant risk to the participant, or interfere with interpretation of study data.
• Presence of a clinically significant finding on echocardiogram (as assessed by the investigator).
• Presence of an abnormal finding on ECG at screening that in the investigator's opinion is clinically significant and/or the following ECG parameters: QTcF interval > 450 milliseconds, QRS interval > 120 milliseconds, PR interval > 220 milliseconds, ECG evidence of Brugada syndrome, atrial fibrillation or atrial flutter, or Mobitz II or higher grade atrioventricular block.
• Current treatment with a potent/strong inhibitor or inducer of CYP3A4 within 5 half-lives before the first dose of study treatment or expected to receive such treatment during the study.
  • Note: Topical ketoconazole is allowed.
• Use of the following medications:
  • Imatinib 30 days prior to baseline (Day 1 visit);
  • Any medication that might interfere with HO formation in the 90 days before baseline (Day 1 visit);
  • Bisphosphonates within 1 year of screening.
• Participation in an investigational drug study for the treatment of FOP or any other indication within 30 days or 5 half-lives (whichever is longer) before baseline (Day 1 visit).
• Planning to receive a live vaccine during the course of the study or within 6 weeks after the last dose of study drug.
• Known or suspected allergy to INCB000928 or any component of the study drug.
• Known history of clinically significant drug or alcohol abuse as defined by the investigator in the l year before baseline (Day 1 visit).
• Chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
• HIV, HBV, or HCV infection.

Note: Successfully treated HCV is allowed.

• Participants with laboratory values at screening defined in Table 7.

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

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

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

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

• Have completed a Corcept-sponsored study of relacorilant in endogenous Cushing syndrome with at least 80% compliance with the dosing schedule.
• According to the Investigator's opinion, will benefit from continuing treatment with relacorilant.

• Premature discontinuation from a relacorilant parent study.
• Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
• Has poorly controlled hypertension.
• Has Stage ≥ 4 renal failure.

Eligibility last updated 2/8/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 4/12/23. Questions regarding updates should be directed to the study team contact.

• Patient must be aged ≥ 18 years at the time of signing the informed consent.  In some countries, parental consent may be required in addition to an assent form for patients who are 18 years of age.
• Patient must have histologically documented diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as defined by a B-cell neoplasm in the World Health Organisation classification scheme except as noted in the exclusion criteria.
• Patient has relapsed after or failed to respond to at least 2 but no more than 5 prior systemic treatment regimens (including investigational therapy) and for whom there is no available therapy expected to improve survival (e.g., standard chemotherapy, autologous stem cell transplantation (SCT), chimeric antigen receptor T cell (CAR-T) cell therapy).
• Documented active disease requiring treatment that is relapsed or refractory defined as: -Recurrence/relapse of disease after response to prior line(s) of therapy.
• Progressive disease (refractory) on/after completion of the treatment regimen preceding entry into the study.
• Must have at least one measurable, fluorodeoxyglucose positron emission tomography (FDG-PET) avid lesion (except for MZL), based on bi-dimensional assessment on PET and computed tomography (CT)/magnetic resonance imaging (MRI) scan. A measurable lesion is defined as:
  • For nodal lesions: longest diameter > 1.5 cm;
  • For extranodal lesions: longest diameter > 1 cm;
  • Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2. Performance status must not have deteriorated by ≥ 2 levels within 2 weeks after providing informed consent.
• Adequate haematologic, hepatic, and renal function.
• Adequate cardiac function as demonstrated by left ventricular ejection fraction > 50% on screening cardiac multigated acquisition, magnetic resonance imaging, or echocardiogram.
• Women of childbearing potential and men should use protocol defined contraceptive measures.
• Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study intervention and admission to the hospital, when required, for administration of study treatment and monitoring.
• All patients must be willing to undergo an incisional or excisional lymph node or tissue biopsy or to provide a lymph node or tissue biopsy from the most recent available archival tissue.
• For inclusion in the genetic component of the study, patients must fulfil protocol defined criteria.

Inclusion Criteria
•Module 1 Additional Inclusion Criteria for Cohort B1 (R/R mantle cell lymphoma [MCL]):

• Histologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, as assessed by Investigator or local pathologist.
• Must have relapsed after or failed to respond to at least 2 prior lines of treatment, including one anti-CD20 monoclonal antibody (mAb) and a Bruton's tyrosine kinase inhibitor.

Additional Inclusion Criteria for Cohort B2 (R/R FL or MZL):

• Histologically confirmed diagnosis of FL Grade 1, 2, or 3a OR histologically confirmed MZL including splenic, nodal, and extranodal subtypes, as assessed by Investigator or local pathologist.
• For FL patients: Previously received at least 2 prior systemic treatment regimens (including anti-CD20 mAb and an alkylating agent).
• For MZL patients: Previously received at least 2 prior lines of systemic therapy including at least one anti-CD20 mAb-directed regimen either as monotherapy or as chemoimmunotherapy (Helicobacter pylori eradication and radiation therapy alone will not be considered a systemic treatment regimen).

Additional Inclusion Criteria for Cohort B3 (R/R DLBCL):

• Histologically confirmed DLBCL (including transformed FL) OR FL Grade 3b.
• Must have received 2 lines of systemic therapy including at least one anti-CD20 mAb-directed regimen and must have failed or are ineligible for stem cell transplantation (if indicated per local institutional guidelines).

• Diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukaemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma.
• High risk of TLS according to Howard modification of Cairo-Bishop criteria and/or the presence of bulky disease.
• Unresolved toxicity from prior anticancer therapy. Patients with Grade 2 neuropathy or Grade 2 alopecia are eligible.
• Active idiopathic thrombocytopenic purpura.
• Active central nervous system (CNS) involvement by lymphoma, leptomeningeal disease or spinal cord compression.
• Known history of infection with human immunodeficiency virus.
• Known serologic status reflecting active hepatitis B or C infection; concurrent infection with cytomegalovirus (CMV).
• Patients must be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and those with active infection in accordance with local testing guidelines will be excluded. -Any evidence of severe or uncontrolled systemic diseases; current unstable or uncompensated respiratory or cardiac conditions; uncontrolled hypertension; history of, or active, bleeding diatheses; uncontrolled active systemic fungal, bacterial, or other infection.
• Any of the following cardiac criteria at screening: patients with a history of myocarditis within one year of study entry, or heart failure; mean resting corrected QT interval (QTcF) ≥ 470 msec obtained from 3 electrocardiograms (ECGs), in the absence of a cardiac pacemaker; any factors that increase the risk of QTc prolongation or risk of arrhythmic events; any clinically important abnormalities in rhythm, conduction or morphology of resting ECG.
• History of another life-threatening malignancy ≤ 2 years prior to first dose of study intervention.
• Any of the following currently or in the 6 months prior to the first dose of study intervention: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.
• Treatment with any of the following:
  • radiotherapy less than 2 weeks prior to the first dose of study intervention; any investigational agents or study drugs from a previous clinical study within ≤ 14 days or 5 half-lives prior to the first dose of study intervention; any other chemotherapy, immunotherapy, immunosuppressant medication or anticancer agents within 21 days of the first dose of study intervention;
  • prior allogenic haematopoietic stem cell transplantation (HSCT) within 6 months from the first dose of study intervention (patients > 6 months after allogenic HSCT are eligible in the absence of active graft-versus host disease and concomitant immune-suppressive therapy). Eligible patients must have stopped immunosuppression at least 2 months prior to study entry; prior cellular therapies such as CAR-T and/or autologous HSCT within 3 months prior to the first dose of study intervention; major surgery ≤ 21 days, or minor surgical procedures ≤ 7 days, prior to the first dose of study intervention; prescription or non-prescription drugs or other products known to be sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, or reversible moderate or strong cytochrome 3A (CYP3A) inhibitors, which cannot be discontinued within 5 half-lives of the first dose of study intervention and withheld throughout the study until 14 days after the last dose of AZD0466; moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5 half-lives plus 12 days of the drug prior to the first dose of study intervention and withheld until 14 days after the last dose of AZD0466; concurrent anticoagulation therapy, including aspirin, which cannot be stopped; medications with known risk of Torsades de Pointes within 5 half-lives of the first dose of study intervention and continuing until 5 half-lives after the last dose of AZD0466.
• Administration of a live, attenuated vaccine within 4 weeks before first dose of study intervention.
• Administration of inactivated vaccines or protein/RNA immunogen vaccines.
• Patients with a known hypersensitivity to polyethylene glycol, pegylated products, or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic.

Exclusion Criteria- Module 1 Additional Exclusion Criteria for Cohort B1:

• Patients with known blastoid or pleiomorphic variant at study entry/most recent relapse.

Additional Exclusion Criteria for Cohort B2:

• Histologically confirmed diagnosis of FL grade 3B.
• Known transformation to aggressive lymphoma; e.g., large cell lymphoma.

Eligibility last updated 2/8/22. Questions regarding updates should be directed to the study team contact.

• Adults over the age of 18 and who are willing and able to give informed consent.
• Willing to participate in all activities related to this study, including trimming chest hair and wearing a reference device and the CPM wearable device.
• Volunteers of any race, any gender.
• Range of physiques.

• Injury or skin disturbance in the area of the test device.
• Pregnant.
• Currently smokes cigarettes.
• Has known respiratory conditions such as:
  • Flu;
  • Pneumonia/bronchitis;
  • Shortness of breath/respiratory distress;
  • Respiratory or lung surgery;
  • Emphysema, COPD, lung disease.
• Has self-reported heart or cardiovascular conditions such as chest pain, AFib, CHF, cardiomyopathy, or other conditions that could interfere with cardiopulmonary function.
• Has other self-reported health conditions that could interfere with the breathing patterns and exercises detailed in the protocol (including wearing a capnography mask).

Eligibility last updated 2/20/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 3/29/23. Questions regarding updates should be directed to the study team contact.

• Written or oral pediatric assent from the subject deemed capable of providing assent and written informed consent from the subject’s parent(s) or legal guardian(s) in accordance with the governing Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and according to local laws and regulations. Informed consent/assent may be done remotely, if allowed per site and remote consenting procedures are in place.
• Completed 12 weeks of treatment (3 weeks titration and 9 weeks maintenance) in Study NBI-827104-CSWS2010.
• Subjects of childbearing potential must agree to use highly effective birth control methods consistently while participating in the study until 90 days after the last dose of the study treatment.
• A female subject of childbearing potential is defined as a subject who has had her first menstrual cycle (ie, menarche). A male subject of childbearing potential is defined as a subject who has reached spermarche.
• Highly effective methods of birth control for female subjects of childbearing potential are:
  • Combined (estrogen and progestogen containing) hormonal contraception or progestogen-only hormonal contraception used with an effective nonhormonal method of contraception (eg, barrier contraception used with spermicide);
  • Intrauterine hormone-releasing system used with an effective nonhormonal method of contraception (eg, barrier contraception used with spermicide);
  • Intrauterine device;
  • Bilateral tubal occlusion;
  • Vasectomized partner;
  • True abstinence from sexual intercourse as the preferred lifestyle;
  • Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) is not acceptable.     
• Female subjects of childbearing potential must have a negative urine pregnancy test at Day 1.
• The acceptable methods of contraception for male subjects of childbearing potential are:
  • Condom with spermicide (cream, spray, foam, gel, suppository, or polymer film);
  • Vasectomy at least 3 months prior to screening with medically confirmed successful procedure;
  • True abstinence from sexual intercourse as the preferred lifestyle. Note that periodic abstinence is not acceptable.
• A subject who becomes of childbearing potential during the study will be required to use contraception as described.
• Willing to comply with all study procedures and restrictions.

• Pregnant or breastfeeding.
• Planned surgical intervention related to structural abnormalities of the brain from screening through the Week 6 Visit.
• Used any active investigational drug other than NBI-827104 in the context of a clinical study within 30 days or 5 half-lives (whichever is longer) before Day 1 or plans to use such an investigational drug (other than NBI-827104) during the study.
• It is anticipated that the subject will require treatment with at least 1 of the prohibited concomitant medications or other restrictions during the specified study time frame.
• Have developed any other disorder for which the treatment takes priority over treatment of EECSWS or is likely to interfere with study treatment or impair treatment compliance.
• The subject or the subject’s parent(s)/caregiver(s) are, in the investigator’s opinion, unlikely to comply with the protocol, including the requirement to travel to the study sites for study visits, or is unsuitable for any reason.

Eligibility last updated 2/18/22. Questions regarding updates should be directed to the study team contact.

• Male or female and ≥ 18 years-of-age at the time of informed consent.
• ECOG Performance status 0 or 1.
• Locally advanced or metastatic resistant or refractory solid tumors.
• Submission of available tumor tissue at screening or willingness to have a biopsy performed if safe and feasible.
• Measurable disease as per RECIST v1.1.
• Ability to swallow and retain oral medications.
• Acceptable hematologic and organ function at screening.
• Negative pregnancy test (serum) for women of childbearing potential (WOCBP) at Screening.
• Resolution of all toxicities of prior therapy or surgical procedures.
• Life expectancy ≥ 12 weeks after the start of the treatment.

• Chemotherapy or small molecule antineoplastic agent given within 21 days or < 5 half- lives, whichever is shorter, prior to first dose of study drug.
• History or current condition, therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment.
• Patients who are pregnant or breastfeeding.
• Known sensitivity to any of the ingredients of RP-6306 or gemcitabine.
• Life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction or other reasons which, in the investigator's opinion, could compromise the participating patient's safety.
• Major surgery within 4 weeks prior to first dose of RP-6306 and gemcitabine.
• Uncontrolled, symptomatic brain metastases.
• Uncontrolled hypertension.
• Moderate or severe hepatic impairment.
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

Eligibility last updated 2/14/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 1/18/23. Questions regarding updates should be directed to the study team contact.

• Patient must be ≥ 18 years and ≤ 39 years of age at registration.
• Patient must have a histologically confirmed diagnosis of primary cancer of any stage within 12 weeks (84 days) at registration.
• Patient must have received, be currently receiving or planning to receive treatment for cancer, including surgery and/or chemotherapy and/or radiation therapy.
• Patient must have an ECOG performance status 0-3.
• Patient must have a life expectancy > 24 months.
• Patient must be able to complete questionnaires in English.
• Patient must have internet access through computer, tablet, or smartphone.
• Patient must have an email address.
• Patient must have a mobile phone able with text messaging capabilities.
• Patient must be able to accurately provide self-report data (e.g., per clinical judgment, cognitive function is intact). Patient must be able to provide informed consent.

• Patient must not have a recurrence or second primary cancer.
• Patient must not have basal cell skin carcinoma.

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

• Male and female, age 18 and older.
• Suspected of having eye tumor.

AIM 1 - SUBSET OF LARGE CHOROIDAL NEVI:

• Lesions with thickness > 1.5 mm and minimum documented stability interval of 2 years.

• Lesions with thickness < 1.5 mm or fewer than 2 years of documented stability.

SUBSET LARGE MELANOMA:

• Choroidal, ciliary body, or ciliochoroidal melanoma in a patient who elected to have enucleation for primary tumor treatment.

• Iris melanoma or melanoma that has undergone prior treatment before enucleation.

PRESUMED CHOROIDAL MELANOMA:

•  Choroidal, ciliary body, or ciliochoroidal melanoma with thickness > 1.5 mm treated by radiation. These lesions may sometimes have biopsy for cytogenetic testing at the time of radiation treatment.

• Iris melanoma, lesions with thickness < 1.5 mm, non-melanoma tumors.

AIM 2

• Orbital mass with completed neuroimaging (typically with MRI) and clinical/MRI suspicion for lymphoma.

• Recent orbital biopsy (within the past 3 months) prior to qHDMI, clinical impression clearly compatible with a non-lymphoma tumor type.

Eligibility last updated 2/18/22. Questions regarding updates should be directed to the study team contact.

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

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

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

• Males and females ≥ 18 years of age
• Have locally advanced or metastatic solid tumor malignancy with measurable disease and be an appropriate candidate for experimental therapy.
• Part A (JSI-1187 Monotherapy Dose Escalation):
  • Histologically or cytologically confirmed MAPK pathway mutation, including hyperactivating pathway mutations or gene fusions; e.g., BRAF (Class I, II or III), RAS (H/K/N), MEK (MAP2K1), RAS-GAP (NF1 loss, RASA1), RAS-GEF, refractory to or relapsed on prior therapy, and have received all available therapy known to confer clinical benefit.
  • Part B (JSI-1187 Plus Dabrafenib Combination Dose Escalation):
    • Histologically or cytologically confirmed BRAF V600-mutated locally advanced or metastatic solid tumor, refractory to, or relapsed on, prior therapy, and have received all available therapy known to confer clinical benefit.
• Part C (JSI-1187 Plus Dabrafenib Expansion Cohorts): Histologically or cytologically confirmed:
  • Cohort 1: BRAF V600-mutated metastatic melanoma after two prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment;
  • Cohort 2: BRAF V600-mutated metastatic melanoma after adjuvant therapy for Stage 3 disease followed by one prior therapy for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab or BRAF/MEK inhibitor treatment;
  • Cohort 3: Either BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC), or BRAF V600-mutated metastatic solid tumor, after 1 or 2 prior therapies.
• MAPK mutation tumor status will be established prior to entry based on previous MAPK pathway mutation reports from a CLIA qualified laboratory, or, if a report is not available, the mutation analysis will be performed at Screening on archival tissue or newly biopsied tumor tissue.
• Have discontinued previous treatments for cancer and have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy to Grade ≤ 1.
• Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2.
• Life expectancy of ≥ 3 months -Subjects with asymptomatic stable, prior or currently treated brain metastases are allowed -Adequate hematologic parameters without ongoing transfusional support:
  • Hemoglobin (Hb) ≥ 9 g/dL -Absolute neutrophil count (ANC) ≥ 1.0 x 10^9 cells/L;
  • Platelets ≥ 75 x 10^9 cells/L -Adequate renal and hepatic function;
  • Creatinine ≤ 1.5 times the upper limit of normal (ULN), or calculated creatinine clearance ≥ 50 mL/minute x 1.73 m^2 per the Cockcroft-Gault formula;
  • Total bilirubin ≤ 2 times the (ULN) unless due to Gilbert's disease;
  • ALT/AST ≤ 2.5 times the ULN, or < 5 times the ULN for subjects with liver metastases.
• Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects must agree to use adequate methods to avoid pregnancy throughout the study and for 28 days after the completion of study treatment.
• Ability to provide written informed consent.

• Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV.
• QT interval corrected for rate (QTc) > 480 msec on the ECG obtained at Screening using Fridericia method for QTc calculation.
• Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, with the exception of anti-microbials that are used as standard of care to prevent or treat infections and other such drugs that are considered by the Investigator to be essential for patient care.
• Medications that are strong inhibitors of CYP3A4 are prohibited during study and for 14 days prior to the first dose of study drug(s).
• Medications that are strong inducers of CYP3A4 are prohibited during study and for 14 days prior to the first dose of study drug(s).
• Medications that are strong inhibitors of BCRP are prohibited during study and for 14 days prior to the first dose of study drugs(s).
• Subjects on dabrafenib (Parts B and C) also are advised to avoid concurrent administration of strong inhibitors of CYP2C8 as these medications may increase the concentration of dabrafenib -History of or current evidence/risk of retinal vein occlusion or central serous retinopathy, or has medically relevant abnormalities identified on screening ophthalmologic examination -Symptomatic central nervous system malignancy or metastasis -Gastrointestinal conditions that could impair absorption of study drug(s).
• Current hematologic malignancies -Second, active primary solid tumor malignancy that, in the judgement of the investigator or Sponsor medical monitor, may affect the interpretation of results.
• Prior malignancies, with the exception of carcinoma in situ of any origin, non-muscle invasive bladder cancer, Gleason 3+3 prostate cancer and prior malignancies in remission whose likelihood of recurrence is very low, as judged by the Sponsor medical monitor.
• Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment within the last week prior to study treatment.
• Other active infection requiring IV antibiotic usage within the last week prior to study treatment.
• Any other medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results.
• Participation within the last 28 days in a clinical trial, or currently enrolled in a clinical trial, involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
• Previously completed or withdrawn from this study or any other study investigating an ERK1/2 inhibitor.
• If female, pregnant, breast-feeding, or planning to become pregnant.

Eligibility last updated 2/24/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 1/25/23. Questions regarding updates should be directed to the study team contact.

Key

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

Eligibility last updated 4/27/23. Questions regarding updates should be directed to the study team contact.

• Men and women ≥ 50 years of age.
• The patient has met eligibility criteria and is planned to undergo LAAO with the WATCHMAN FLX device as part of clinical care.
• The patient is able and willing to undergo non-invasive cognitive testing using the Viewmind headset by a trained personal.
• The patient is able to give informed consent for the procedure.

• The patient unwilling or unable to complete cognitive testing using the specialized virtual reality googles.
• Primary language is not English.

Eligibility last updated 3/11/22. Questions regarding updates should be directed to the study team contact.