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

• Any patient undergoing surgery for intralesional resection of neoplasm such as tumors of the spine/extremities or metastatic disease.

• Patients undergoing surgery with an expected blood loss of less than 135cc.
• Provisions for inclusion of minorities: 
  • Subjects will be enrolled prospectively irrespective of their sex/gender, race, and ethnicity in order to improve generalizability.        

Eligibility last updated 2/21/22. Questions regarding updates should be directed to the study team contact.

• Age 21-65.
• BMI ≥ 30 and ≤ 40 kg/m² .
• Willingness to comply with the substantial lifelong dietary restrictions required by the procedure.
• 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, and 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. 

• History of foregut or gastrointestinal (GI) surgery (except uncomplicated cholecystectomy or appendectomy).
• Prior gastrointestinal surgery with sequelae; i.e., obstruction, and/or adhesive peritonitis or known abdominal adhesions.  
• Prior open or laparoscopic bariatric surgery.  
• Prior surgery of any kind on the esophagus, stomach or any type of hiatal hernia surgery. 
• Any inflammatory disease of the gastrointestinal tract including severe (LA Grade C or D) 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. 
• Gastrointestinal stromal tumors, history of premalignant gastric lesions (intestinal metaplasia), history of familial and nan-familial adenomatous syndromes.  
• A gastric mass or gastric polyps > 1 cm in size.  
• A hiatal hernia > 4cm of axial displacement of the z-line above the diaphragm or severe or intractable gastro-esophageal reflux symptoms.  
• A structural abnormality in the esophagus or pharynx such as a stricture or diverticulum that could impede passage of the endoscope.  
• Achalasia or any other severe esophageal motility disorder.
• Severe coagulopathy. 
• Insulin-dependent diabetes (either Type 1 or Type 2) or a significant likelihood of requiring insulin treatment in the following 12 months or a HgbA1C ≥ 9. 
• 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.
• Use of an intragastric device prior to this study due to the increased thickness of the stomach wall preventing effective suturing.  
• Active psychological issues preventing participation in a life-style modification program as determined by a psychologist.
• 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 high dose aspirin (> 80 mg daily), anti-inflammatory agents, anticoagulants or other gastric irritants.  
• Patients who are unable or unwilling to take prescribed proton pump inhibitor medication.
• Patients who are pregnant or breast-feeding.  
• Patients currently taking weight-loss medications or other therapies for weight loss within the prior 6 months. 
• 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 taking medications on specified hourly intervals that may be affected by changes to gastric emptying, such as anti-seizure or anti-arrhythmic medications.
• Subjects who are taking corticosteroids, immunosuppressants, and narcotics.
• Symptomatic congestive heart failure, cardiac arrhythmia or unstable coronary artery disease.  
• Pre-existing respiratory disease such as moderate or severe chronic obstructive pulmonary disease (COPD) requiring steroids, pneumonia or cancer.  
• Diagnosis of autoimmune connective tissue disorder (e.g. lupus, erythematous, scleroderma) or immunocompromised.  
• Specific diagnosed genetic disorder such as Prader Willi syndrome. 
• Eating disorders including night eating syndrome (NES), bulimia, binge eating disorder, or compulsive overeating. 
• Known history of endocrine disorders affecting weight such as uncontrolled hypothyroidism. 
• If deemed medically inappropriate or ineligible by investigator. 

Eligibility last updated 2/1/22. Questions regarding updates should be directed to the study team contact.

• 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.

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.

• 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.

• Has a histologically or cytologically confirmed diagnosis of Stage IV (T any, N any, M1a, M1b, M1c
  •AJCC eighth Edition) squamous or nonsquamous NSCLC.
  • Note: Mixed tumors will be characterized by the predominant cell type; if small cell elements are present, the participant is ineligible.
• Has measurable disease based on RECIST 1.1, as determined by the local site assessment.
  • Note: Measurable disease is defined as having at least 1 measurable lesion by CT or MRI per RECIST 1.1. Lesions that appear measurable but are situated in a previously irradiated area can be considered measurable (eligible for selection as target lesions) if they have shown documented growth since the completion of radiation.
• Has provided tumor tissue (post diagnosis of metastatic disease is preferred) for determination of PD-L1 status before randomization.
  • Note: Assessment of PD-L1 expression must be made from provided archival tumor tissue sample or newly obtained core or incisional or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Details pertaining to tumor tissue submission can be found in the Laboratory Manual.
• Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of the absence of tumor-activating EGFR mutations [e.g., DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements).
  • Note: If participant’s tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines.
• Has not received prior systemic treatment for metastatic NSCLC.
• Is male or female, from ≥ 18 years of age inclusive, at the time of signing the informed consent.
• Has an ECOG PS of 0 or 1 assessed within 7 days before randomization.
• Has a life expectancy of at least 3 months.
• If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
  • Chemotherapy: at least 95 days from the last dose;
  • Refrain from donating sperm; PLUS either:
  • Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent; OR
  • Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview as detailed below:
  • Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
  • Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penilevaginal penetration.
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies:
  • Not a WOCBP; OR
  • Is a WOCBP and:
  • Uses a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
    • MK-7684A/pembrolizumab: 120 days;
    • Chemotherapy: 180 days.
• The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• Has a negative highly sensitive pregnancy test ( as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, 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. 
• Abstains from breastfeeding during the study intervention period and for at least 120 days after the last dose of study intervention.
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
• The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR.  However, the participant may participate in the study without participating in FBR.
• Has adequate organ function. Specimens must be collected within 10 days before the start of study intervention.
• Absolute neutrophil count (ANC) ≥ 1500/μL.
• Platelets ≥ 100 000/μL.
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La.
• Estimated creatinine clearance using the Cockcroft-Gault equation.
• To initiate treatment with carboplatin or cisplatin, CrCl must be ≥ 60 mL/min
• Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN.
• AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases).
• International normalized ratio (INR) OR prothrombin time (PT).
• Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=absolute neutrophil count; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
• Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
• Estimated creatinine clearance using Cockcroft-Gault:
  • (140-age [years] × weight (kg) (×F)*Serum creatinine (mg/dL) × 72 *where F = 0.85 for females and F = 1 for males
  • Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements are to be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
  • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e., without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.
• Participants with asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate.
• Severe hypersensitivity (≥ Grade 3) to MK-7684, MK-7684A, pembrolizumab, chemotherapy components, and/or any of its excipients.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study medication.
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • Note: Lymphangitic spread of the NSCLC is not exclusionary.
• Active infection requiring systemic therapy.
• Known history of HIV infection. No HIV testing is required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• History or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
• Received prior therapy with an anti-TIGIT, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
• Received prior systemic anticancer therapy for metastatic disease.
  • Note: Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months before the development of metastatic disease.
• If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the operation before starting study intervention.
• Received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis. 
  • Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• Received radiation therapy to the lung that is > 30 Gray within 6 months of the first dose of study intervention.
• Received a live or live attenuated vaccine within 30 days before the first dose of study
• intervention. Administration of killed vaccines are allowed. 
• Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤ 1.3 g/day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• History of allogenic tissue/solid organ transplant.

Eligibility last updated 2/18/22. 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.

• 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).

• Participant (male or female) must be 18 years or older at the time of signing the informed consent.
• Participants who are ≥ 40 kg at Screening Visit 1.
• EGPA diagnosis: Participants who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia [Jennette, 2013] defined in this study as > 1.0x10^9/L and/or > 10% of leucocytes plus at least 2 of the following additional features of EGPA:
  • a biopsy showing histopathological evidence of eosinophilic vasculitis, or perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation;
  • neuropathy, mono or poly (motor deficit or nerve conduction abnormality);
  • pulmonary infiltrates, non-fixed;
  • sino-nasal abnormality;
  • cardiomyopathy (established by echocardiography or magnetic resonance imaging [MRI]);
  • glomerulonephritis (haematuria, red cell casts, proteinuria);
  • alveolar haemorrhage (by bronchoalveolar lavage);
  • palpable purpura;
  • ANCA positive Myeloperoxidase (MPO) or Proteinase 3 (PR3).
• History of relapsing OR refractory disease defined as:
  • Relapsing disease: Participants must have a history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation/increased dose of immunosuppressive therapy or inpatient hospitalisation due to EGPA) within the past 2 years. EGPA relapse should have occurred at least 12 weeks or more prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent of) ≥ 7.5 mg/day;
  • Refractory disease: Defined as either failure to attain remission (BVAS=0 and OCS dose ≤ 7.5 mg/day prednisolone or equivalent) within the last 6 months prior to Screening Visit 1 and following induction treatment with a standard OCS regimen, administered for at least 3 months OR participants with recurrence of EGPA symptoms within 6 months prior to Screening (Visit 1) whilst tapering OCS and occurring at any dose level ≥7.5 mg/day prednisolone or equivalent.
    • NOTE: Recurrent symptoms of EGPA do not necessarily need to meet the protocol definition of relapse.
• Corticosteroid therapy: Participants must be on a stable dose of oral prednisolone or prednisone of ≥7.5 mg/day (but not > 50 mg/day) for at least 4 weeks prior to Baseline (Visit 2).
• Immunosuppressive therapy: If receiving immunosuppressive therapy (excluding cyclophosphamide) the dosage must be stable for the 4 weeks prior to Baseline (Visit 2) and during the study.
• 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 nonchildbearing 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 the following durations (whichever is greater)
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

• GPA or MPA: Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegener’s granulomatosis) or microscopic polyangiitis (MPA).
• EULAR defined organ-threatening EGPA: Organ-threatening EGPA as per EULAR criteria, i.e., organ failure due to active vasculitis, creatinine > 5.8 g/dL (> 513 µmol/L) within 3 months prior to Screening (Visit 1).
• Life-threatening EGPA: Imminently life-threatening EGPA disease defined as any of the following within 3 months prior to Screening (Visit 1).
• Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening. Participants that had localised carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded).
• Liver Disease: Alanine aminotransferase (ALT) > 2 x upper limit of normal (ULN) or if participant is on background methotrexate or azathioprine > 3 x ULN, AST > 2 x ULN or if participant is on background methotrexate or azathioprine > 3 x ULN, Alkaline Phosphatase ≥ 2.0 x ULN , Total bilirubin > 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%), 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.
• Cardiovascular: Participants who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to: Known ejection fraction of < 20%, OR Severe heart failure that meets New York Heart Association Class IV, OR Hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III OR Myocardial infarction or angina diagnosed less than 3 months prior to or at Screening Visit 1 ORUncontrolled life threatening arrythmia within 3 months prior to or at Screening Visit 1).
• Other Concurrent Medical Conditions: Participants who have known, pre‑existing, clinically significant cardiac, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment.
• Laboratory abnormality: Evidence of clinically significant abnormality in the haematological, biochemical or urinalysis screen at Visit 1, as judged by the investigator.
• Infectious disease: Chronic or ongoing active infectious disease requiring systemic treatment.
• Parasitic infection: Participants with a known, pre-existing parasitic infestation within 6 months prior to Screening Visit 1.
• Immunodeficiency: A known immunodeficiency (e.g., human immunodeficiency virus – HIV), other than that explained by the use of OCS or other immunosuppressants taken as therapy for EGPA.
• COVID-19: Participants that, according to the investigator's medical judgment, are likely to have active COVID-19 infection. 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.
• Hypersensitivity: Participants with a known allergy or intolerance to a monoclonal antibody or biologic therapy or any of the excipients of the investigational products.
• Monoclonal antibodies targeting IL-5/5R: Participants who have a previous documented failure with anti-IL-5/5R therapy.
• Participants who have received treatment with investigational drug within the past 30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to Visit 1 (this also includes investigational formulations of marketed products).  Participants who are currently participating in any other interventional clinical study.
• Other prohibited medications: Participants receiving any of the following:
  • Oral corticosteroids: Participant requires an oral corticosteroid dose of > 50 mg/day prednisolone/prednisone in the 4-week period prior to Baseline (Visit 2);
  • Intravenous, intramuscular or SC corticosteroids in the 4-week period prior to Baseline (Visit 2);
  • Omalizumab within 130 days prior to Screening (Visit 1);
  • Cyclophosphamide:  oral CYC within 4 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to Baseline (Visit 2), if their total WBC is ≥ 4 x10^9/L (measured using the local laboratory if necessary);
  • Rituximab within 12 months prior to Screening (Visit 1); in addition, the Participant must have shown recovery of peripheral B-cell count to within the normal range;
  • IV or SC immunoglobulin within 6 months prior to Screening (Visit 1); For China and Japan only within 12 weeks prior to Screening (Visit 1);
  • Interferon-α within 6 months prior to Screening Visit 1;
  • Anti-TNF therapy within 12 weeks prior to Screening Visit 1;
  • Anti-CD52 (alemtuzumab) within 6 months prior to Screening Visit 1.
• Previous participation: Previously participated in any study with mepolizumab, reslizumab, or benralizumab and received study intervention (including placebo) within 6 months prior to Screening Visit 1.
• ECG Assessment: QTcF ≥ 450 msec or QTcF ≥ 480 msec for participants with Bundle Branch Block at Screening Visit 1.
• Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
• Pregnancy: Participants who are pregnant or breastfeeding. Participants should not be enrolled if they plan to become pregnant during the time of study participation.
• Adherence: Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.

Eligibility last updated 2/17/22. 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.

• Males and females between 18 and 85 years of age, inclusive, at screening.
• Body mass index < 35 kg/m^2.
• Diagnosed with HCM per the following criteria:
  • Has LV hypertrophy and non-dilated LV chamber in the absence of other cardiac disease; and 
  • Has an end-diastolic LV wall thickness as measured by the echocardiography core laboratory of:
    • ≥ 15 mm in one or more myocardial segments; OR
    • ≥ 13 mm in one or more wall segments and a known-disease-causing gene mutation or positive family history of HCM.
• Has resting LVOT-G ≥ 30 mmHg and post-Valsalva LVOT G ≥ 50 mmHg during screening as determined by the echocardiography core laboratory.
• LVEF ≥ 60% at screening as determined by the echocardiography core laboratory.
• NYHA Functional Class II or III at screening.
• Hemoglobin ≥ 10g/dL at screening.
• Respiratory exchange ratio (RER) ≥ 1.05 and pVO2 < 80% predicted on the screening CPET per the core laboratory.
• Patients on beta-blockers, verapamil, diltiazem, or disopyramide should have been on stable doses for > 6 weeks prior to randomization and anticipate remaining on the same medication regimen during the trial. Patients treated with disopyramide must also be concomitantly treated with a beta blocker and/or calcium channel blocker.

• Known or suspected infiltrative, genetic or storage disorder causing cardiac hypertrophy that mimics oHCM (e.g., Noonan syndrome, Fabry disease, amyloidosis).
• Significant valvular heart disease (per investigator judgment).
• Moderate-severe valvular aortic stenosis.
• Moderate-severe mitral regurgitation not due to systolic anterior motion of the mitral valve.
• History of LV systolic dysfunction (LVEF < 45%) or stress cardiomyopathy at any time during their clinical course.
• Inability to exercise on a treadmill or bicycle (e.g., orthopedic limitations).
• Has been treated with septal reduction therapy (surgical myectomy or percutaneous alcohol septal ablation) or has plans for either treatment during the trial period.
• Documented paroxysmal atrial fibrillation during the screening period.
• Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (e.g., direct-current cardioversion, atrial fibrillation ablation procedure, or antiarrhythmic therapy) ≤ 6 months prior to screening. (This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and adequately rate-controlled for > 6 months).
• History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior to screening.
• Has received prior treatment with CK-3773274 or mavacamten.

Eligibility last updated 2/24/22. 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.

• Adult (18 years or older).
• Able to provide informed consent 
• Able to provide samples in English.
• U.S. based patient.

• Age < 18 years of age.
• Unable to provide samples in English (i.e., need for interpreter flag in Epic).
• Nonverbal / No speech.
• HPP (High Profile Patient) status.
• International patient.

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

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

Eligibility last updated 2/8/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 10/18/22. Questions regarding updates should be directed to the study team contact.