• 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

• Patients must meet all of the following criteria to be included in the study:
  • Children ages 0-18 years at the time of phase I evaluation.
  • Referral to Epilepsy Monitoring Unit for presurgical evaluation (phase I) for treatment of epilepsy; and/or
  • Patients presented at a multidisciplinary conference of providers for consideration of epilepsy surgery; and/or
  • Patients undergoing a surgical procedure for treatment of epilepsy.

• Patients who meet any of the following exclusion criteria will not be included in the study:
  • Patients that are admitted for a phase I evaluation but without available data (i.e., data was lost or is not attainable. For patients admitted for phase I and soon after deemed not surgical candidates, data will still be collected).

• Male or female ≥ 18 years.
• Willing and able to provide signed and dated informed consent prior to any study-related procedures and willing and able to comply with all study procedures.
• Histologically/cytologically confirmed, locally advanced unresectable or metastatic solid tumors and lymphomas that are refractory or intolerant to standard of care therapy, or for which no standard therapy exists. Patients should, in the judgement of the investigator, be deemed not appropriate for any other approved therapy with established benefit for that indication.
• Evaluable disease per RECIST v1.1 for solid tumors or per Lugano 2014 criteria for lymphoma.
• ECOG performance status 0 – 1.
• Life expectancy ≥ 3 months.
• Adequate hepatic function as evidenced by meeting all the following requirements:
  • Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3xULN with documented Gilbert’s syndrome;
  • Aspartate aminotransferase      (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; AST and ALT ≤ 5 × ULN if liver metastases are present..
• Serum creatinine < 1.5 × ULN OR calculated creatinine clearance (CrCL) > 40 mL/min (Cockroft-Gault Equation).
• Hematological function defined as:
  • Absolute neutrophil count ≥ 1.5 × 10^9/L without growth factor support in the 2 weeks prior to screening;
  • Platelet count ≥ 100 × 10^9/L without transfusion in the 2 weeks prior to screening;
  • Hemoglobin ≥ 10 g/dL without transfusion in the 2 weeks prior to screening.
• Prothrombin time, international normalized ratio or activated partial thromboplastin time < 1.5 × ULN.
• Recovery to Grade 0-1, from adverse events related to prior anticancer therapy except alopecia, ≤ Grade 2 sensory neuropathy, lymphopenia, and endocrinopathies controlled with hormone replacement therapy.
• Archival tissue will be requested from all subjects enrolled in the dose escalation cohort for biomarker testing. If archival tissue is not available, a fresh biopsy, taken from a readily accessible tumor lesion will be obtained, unless the physician feels that collecting the biopsy would pose an unacceptable risk to the subject. Subjects who cannot provide archival tissue or fresh biopsies may still be eligible for enrollment into the dose escalation cohort. Fresh tumor biopsies collected pre- treatment at baseline and post-treatment at week 8 are highly recommended but are not required in the dose escalation cohort.
• For Part 3, the pharmacodynamic (PD)/dose expansion cohort, all subjects will be required to provide both pre- and post- treatment biopsies for biomarker analysis as follows:
  • pre- treatment fresh tumor biopsies collected at baseline (during screening); and
  • post-treatment biopsies collected during week. 
• It is also requested that all patients from the PD cohort provide archival tissues (FFPE blocks or 10 unstained sections) if available for biomarker analysis. End of study biopsies are highly recommended but are not required. Subjects entering Part 3 are required to have a readily accessible tumor lesion.
  • Note: The PD cohort will only include patients enrolled in the US, and Chinese patients will not be included in Part 3 given the extensive nature of exploratory molecular analysis that will be required).

• Brain metastases unless patients who are stable treated and off steroids for at least 2 weeks prior to screening or primary brain tumors.
• Red blood cells transfusion dependence.
• History of hemolytic anemia or Evans syndrome in the last 6 months.
• Positive direct antiglobulin test (DAT).
• Severe cardiovascular disease, including cerebrovascular accident (CVA), transient ischemic attack (TIA), myocardial infarction, or unstable angina within 6 months of screening; NYHA class II-IV heart failure within 6 months of screening; Uncontrolled arrhythmia within 6 months of screening.
• History of deep vein thrombosis within 3 months or pulmonary embolism within 6 months of screening.
• Use of anticoagulants or anti-platelet agents (Aspirin ≤ 100 mg daily will be allowed, low molecular weight heparin is also allowed).
• Active infection requiring intravenous therapy within 2 weeks prior to screening.
• Subject with known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or known active or chronic hepatitis B or C infection.
• Anticancer therapy or radiation therapy within 5 half-lives or 4 weeks (whichever is shorter) prior to screening; Palliative radiotherapy within 2 weeks prior to screening.
• Previous exposure to any anti-CD-47 monoclonal antibody or SIRPα antibody.
• Major surgery within 4 weeks prior to screening; minor surgery within 2 weeks prior to screening.
• Allergy to study drug or components of its formulation.
• Pregnant or breast-feeding females.
• Women of reproductive potential who do not consent to use two highly effective methods of birth control (including one barrier method) during treatment and for an additional 180 days after the last administration of study drug. Women of reproductive potential are those who have:
  • not been post- menopausal for at least 12 months and who do not have an FSH level consistent with post-menopausal status; or
  • who have not undergone tubal occlusion, hysterectomy, or bilateral salpingectomy.
• Men with a partner of childbearing potential who do not consent to use two highly effective methods of birth control (including one barrier method) during treatment and for an additional 180 days after the last administration of study drug.
• Any other serious underlying medical (e.g. uncontrolled diabetes mellitus, uncontrolled hypertension, active gastric ulcer, uncontrolled seizures, cerebrovascular incidents, gastrointestinal bleeding, severe signs and symptoms of coagulation and clotting disorders), psychiatric, psychological, familial or geographical condition that, in the judgment of the investigator, may interfere with the planned staging, treatment and follow-up, affect subject compliance or place the subject at high risk from treatment-related complications.
• Symptomatic intrinsic lung disease (chronic obstructive pulmonary disease, pulmonary fibrosis).

• The subjects will be between 45-90 years old for both genders.
• Post-menopausal women.
• Subjects must be able to provide written informed consent.

• Subjects younger than 45 years old.
• Subjects with a BMI > 40.
• Subjects with a history of bariatric surgery.
• Subjects with a history of carotid surgery.
• Subjects not able to provide written consent.
• Vulnerable populations such as neonates, children, pregnant women, and prisoners.

• Patient and/or authorized representative must be willing and able to give informed consent/assent and any authorizations required by local law for participation in the study.
• Patient and their caregiver must be willing and able (in the Investigator’s opinion) to comply with all protocol requirements.
• Patient must be between 2 and 18 years (inclusive) of age at Screening.
• Patient must have DS as defined by:
  • Onset prior to 12 months of age with recurrent focal motor or hemiconvulsive or generalized tonic-clonic seizures, which are often prolonged and triggered by hyperthermia;
  • No past history of causal magnetic resonance imaging (MRI) lesion (MRI not required to confirm absence of lesion);
  • No other known etiology;
  • Normal development at seizure onset.
• Patient must have a documented pathogenic, likely pathogenic variant, or variant of uncertain significance in the SCN1A gene. Patients who have SCN1A testing results of Negative (no variants of clinical significance identified) cannot be enrolled.
• Patient has had at least 2 prior treatments for epilepsy that either had lack of adequate seizure control (requiring an additional antiepileptic drug [AED]) or had to be discontinued due to an AE(s).
• Patient must be experiencing 4 or more convulsive seizures (Hemiclonic, Focal With Motor Signs, Focal To Bilateral Tonic Clonic Convulsion, Generalized Tonic Clonic Convulsion, Tonic, Tonic/Atonic [Drop Attacks], and Clonic) during the initial 28 days of the Observation Period.
• Patient must currently be taking at least one AED at a dose which has been stable for at least 4 weeks prior to Screening.
• All epilepsy medications or interventions for epilepsy (including ketogenic diet or vagal nerve stimulator) must have been stable (including total daily dose and setting) for at least 4 weeks prior to Screening. Vagal nerve stimulator implantation must have occurred at least 6 months prior to Screening.
• Any marijuana- or cannabinoid-based product or medication is allowed but treatment must have been stable for at least 4 weeks prior to Screening, including supplier, ratio, and dose.
• Patient must meet age-appropriate institutional guidelines for intrathecal (IT) drug administration procedures.
• Patient and/or family (or caretaker) must be sufficiently fluent in English or local language to be able to complete questionnaires relevant to this study.
• Patient must have negative pregnancy test at Screening and at Baseline (Day -1) if female of childbearing potential.

• Patient has one of the following mutations in the SCN1A gene:
  • Thr226Met, Leu263Val, Val422Leu, Thr1174Ser, Trp1204Arg, Pro1345Ser, Gln1489Lys, Phe1499Leu, Arg1575Cys, Val1611Phe, Leu1624Pro, Arg1648Cys, Leu1649Gln, Leu1670Trp, Gly1674Arg, or Asp1866Tyr.
• Patient has a known pathogenic mutation in another gene that causes epilepsy. (The pathogenic mutation must be homozygous in cases of known recessive disease).
• Patient is currently being treated with an AED acting primarily as a sodium channel blocker, as maintenance treatment including:
  • phenytoin, carbamazepine, oxcarbazepine, lamotrigine, lacosamide, or rufinamide.
• Patient has clinically significant unstable medical conditions other than epilepsy.
• Patient has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to Screening or prior to dosing on Day 1, other than epilepsy.
• Patient has had clinically relevant symptoms or a clinically significant illness (in the Judgement of the Investigator) in the 4 weeks prior to Screening through prior to dosing on Day 1, other than epilepsy. This includes the presence of an active infection requiring systemic antiviral or antimicrobial therapy.
• Patient has a history of brain or spinal cord disease (other than epilepsy or DS) or a history of bacterial meningitis or brain malformation.
• Patient has a spinal deformity or other condition that may alter the free flow of CSF or has an implanted CSF drainage shunt.
• Patient has clinically significant (in the judgment of the Investigator) abnormal laboratory values at Screening or prior to dosing on Day 1.
• Patient has aspartate aminotransferase or alanine aminotransferase > 2.5-fold upper limit of normal (ULN), serum creatinine >ULN or platelet count < 100 platelets per µL at Screening and upon repeat testing.
• Patient has clinically relevant abnormalities in the 12-lead ECG measured at Screening or prior to dosing on Day -1.
• Patient has a psychiatric or behavioral disorder which, in the opinion of the Investigator, may interfere with the patient’s participation in the study.
• Patient is currently taking or within 4 weeks prior to Day 1, Visit 1 has taken any anticoagulant (including but not limited to heparins, warfarin and other vitamin K antagonists, dabigatran, rivaroxaban and apixaban), or within 7 days prior to Day 1, Visit 1 has taken any antiplatelet (including but not limited to aspirin, non-steroidal anti-inflammatory drugs, clopidogrel, ticlopidine. and dipyridamole).
• Patient is a female of childbearing potential, or patient is a fertile male with female partner(s) of childbearing potential, unless willing to ensure that they or their partners use highly effective contraception throughout the duration of the study and for at least 6 months after their last dose of STK-001.
• Female patient who is pregnant, lactating, or planning pregnancy during the course of the study and for 3 months thereafter.
• Patient who is currently enrolled in or has been part of a blinded clinical study involving an investigational medicinal product within  2 months (or 5 half-lives, whichever is longer) prior to Screening.
• Patient has been part of an interventional clinical study in which an investigational gene therapy or in which STK-001 was administered.
• Patient has any other significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, may influence the results of the study, or may affect the patient’s ability to participate in the study.

Eligibility last updated 1/20/22. Questions regarding updates should be directed to the study team contact.

• Adults self-referred or referred by their physicians starting a senotherapeutic intervention.
• Any individual with senescence-associated medical conditions as defined above, refractory to current standards or care, or without known treatments.
• Any individual taking senotherapeutic agents or performing dietary restriction for any reason.

• Absolute contraindications to indicated senotherapeutic agents due to drug-drug or other interactions.
• Pregnancy or breast-feeding.
• Clinically significant dehydration, infection, renal or hepatic insufficiency.
• Excessive acute or chronic alcohol use.
• Acutely ill individuals requiring hospitalization, emergency, or urgent care.

• Male and female subjects, aged 18 – 65 years, inclusive.
• No medical problems or chronic diseases, specifically, no type 2 diabetes mellitus.
• Body Mass Index (BMI) of ≥ 18 and ≤ 35 kg/m^2 (BMI = weight (kg)/ [height (m)]^2).
• Subjects must agree to the following study restrictions: 
  • Males of procreative capacity (not surgically sterile) will use an acceptable method of contraception from randomization through 1 month following the last dose of study medication. Examples of acceptable contraception for males include abstinence, use of a barrier method, or sterilized or post-menopausal partner;
  • Females of child-bearing potential (not surgically sterile or post-menopausal, defined as 12 months without menses) will use an acceptable method of contraception from 1 month prior to randomization (or screening, if earlier) through 1 month following the last dose of study medication. Examples of acceptable methods of contraception for females include abstinence, double barrier method, IUD, hormonal contraception, or sterilized partner.
• Ability and acceptance to provide written informed consent.
• Willing to participate in the pharmacogenomics sample collection.
• Willing and able to comply with all study requirements and restrictions.
• Willing to not participate in any other interventional trial for the duration of their participation.

• Unable or unwilling to provide informed consent or to comply with study procedures.
• Unwilling to agree to provide pharmacogenomics sample.
• Diagnosis of gastrointestinal diseases.
• Structural or metabolic diseases that affect the GI system.
• Unable to avoid the following over-the-counter medications 48 hours prior to the receipt.
• of study medication and throughout the study:
  • Medications that alter GI transit including laxatives, magnesium and aluminum containing antacids, prokinetics, erythromycin;
  • Analgesic drugs including NSAIDs and COX-2 inhibitors.
    • NOTE:  Stable doses of thyroid replacement, estrogen replacement, low-dose aspirin for cardioprotection, and birth control are permissible. 
• History of recent surgery (within 60 days of screening).
• Pregnant or nursing.
• History of intolerance and/or hypersensitivity to medications similar to tradipitant and its accompanying excipients.
• History (including family history) or current evidence of congenital long QT syndrome or known acquired QT interval prolongation (including QTcF > 450 in males or > 470 in females at screening).
• History of suicide attempt and/or suicidal ideation (of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS)) within 2 years of screening or subject is at risk of suicide at Screening or Baseline visits, in the opinion of the investigator.
• Recent history (within six months of screening) of Alcohol Use Disorder or Substance Use Disorder which may include a positive drug screen at the Screening visit.
• Acute or chronic illness or history of illness, which in the opinion of the investigator could pose a threat or harm to the subject or obscure interpretation of laboratory test results or interpretation of study data such as frequent angina, Class III or IV congestive heart failure, any impairment of renal or hepatic function, poorly controlled diabetes, etc.
• Indication of impaired liver function (including values for AST, ALT, or bilirubin > 2 times the Upper Limit of Normal, unless isolated bilirubin > 2 x ULN due solely to Gilbert’s syndrome).
• Has a creatinine level > 2 x ULN.
• Anyone affiliated as a member of the investigative team or sponsor and/or anyone who may consent under duress.
• Any other reason as determined by the Investigator which may lead to an unfavorable risk-benefit of study participation, may interfere with study compliance, or may confound study results. 

• Subject has histologically confirmed diagnosis of advanced (loco-regionally recurrent and not amenable to curative therapy, or metastatic (stage IV)) TNBC.
• Subject has either a measurable disease per RECIST 1.1 criteria or, if no measurable disease is present, then at least one predominantly lytic bone lesion or mixed lytic-blastic bone lesion with identifiable soft tissue component (that can be evaluated by CT/MRI) must be present Part B1: patients must have measurable disease.
• Subject has adequate tumor tissue to identify the PIK3CA mutation status (either carrying a mutation or without a mutation) and the PTEN loss status; both of which will determine whether the subject can be allocated to Part A
• PIK3CA mutation regardless of PTEN status; or to Part B.
• PTEN loss without a PIK3CA mutation.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Subject has received no more than one line of therapy for metastatic disease.
• Subject has adequate bone marrow and organ function

• Subject has received prior treatment with any PI3K, mTOR or AKT inhibitor.
• Subject has a known hypersensitivity to alpelisib, nab-paclitaxel or to any of their excipients.
• Subject has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤ 1; with the exception of alopecia.
• Subject has central nervous system (CNS) involvement.
• Subject with an established diagnosis of diabetes mellitus type I or uncontrolled type II based on Fasting Plasma Glucose and HbA1c.
• Subject has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) based on investigator discretion.
• Subject has a history of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis.
• Subject has currently documented pneumonitis/interstitial lung disease.
• Subject has a history of severe cutaneous reactions, such as Steven-Johnson Syndrome (SJS), erythema multiforme (EM),Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS).
• Subject with unresolved osteonecrosis of the jaw.
• Other protocol-defined inclusion/exclusion criteria apply.

Phase 1 Dose Escalation

• Have a histologically or pathologically documented, locallyadvanced or metastatic solid tumor for which standard curative measures do not exist or are no longer effective, which may include prior immunotherapy. Preferred indications include: RCC, mesothelioma, NSCLC, cSCC, MSS-CRC, uveal melanoma, malignant melanoma, cervical adenocarcinoma, and CCA.

Phase 2a Dose Expansion

• Have a histologically or cytologically confirmed advanced (metastatic and/or unresectable) solid tumor listed below, that is incurable:
• Advanced (unresectable) or metastatic, intra or extra hepatic adenocarcinoma originating from the bile duct, CCA (Cohort 1) having progressed on at least 1 line of systemic therapy (including targeted therapy if eligible);
• Locally advanced metastatic cutaneous melanoma (Cohort 2) that has failed antiPD-1 or anti-PDL1 therapy (+/- anti-CTLA-4 therapy) and if BRAF+, having failed a BRAF/ +/-MEK inhibitor;
• Locally advanced or metastatic cSCC (Cohort 3) that has not received systemic therapy (e.g., local resection or local topical therapy is permitted);
• Locally advanced or metastatic MSS-CRC (Cohort 4) patients that have progressed on at least 2 prior lines of systemic therapy which should include irinotecan and oxaliplatin +/- targeted therapy if warranted.
  • Note: MSS disease is determined by an approved diagnostic test for identification of patients without a microsatellite instability (MSI) positive biomarker. This testing is performed locally.
• Have measurable disease based on RECIST 1.1 criteria as determined by the Investigator.
  • Note: In the event all measurable disease is situated in a previously irradiated area, these lesions are only considered measurable if progression has been demonstrated post irradiation treatment.
• Have at least one tumor amenable to safe ITu injections (Arm A, Arm B, and Phase 2a only) and biopsies (all Arms and Cohorts). Refer to the ITu Injection Procedure and Biopsy Guidance Manual for information on tumor selection, tumor size, and other procedural recommendations.
• Have ECOG performance status 0 or 1.
• Demonstrate adequate organ function:
  • WBC count ≥ 2,000 cells/mm^3;
  • ANC ≥ 1,000 cells/mm^3;
  • Hgb ≥ 8 g/dL or ≥ 4.96 mmol/L;
  • Platelet count ≥ 100,000 platelets/mm^3 (untransfused);
  • Total bilirubin ≤ 1.5× ULN;
  • AST ≤ 3× ULN and ALT ≤ 3× ULN;
  • Serum chemistries: Sodium, potassium, and calcium WNL or Grade 1;
  • Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min for patient with creatinine levels > 1.5 × institutional ULN according to Cockcroft-Gault formula.
• For ITu Arms (Arm A & B) Only: INR and aPTT WNL For IV Arms (Arm C & D) Only: INR and aPTT ≤ 1.5 ULN.
  • Note: All patients must be able to suspend anticoagulant therapy for study specific biopsies and ITu injections.
• To prevent the risk of environmental shedding, all patients must be willing to use barrier contraception during sexual activity, starting with Day 1 through 6 weeks after the last dose of TBio-6517. Additionally, to prevent pregnancy, patients who are able to conceive or father children must use a highly effective contraction method during sexual activity starting with Screening through 120 days after the last study treatment, including pembrolizumab.
• Be willing and able to attend protocol-specified visits, complete protocol procedures, and adhere to post-treatment care instructions within the informed consent to minimize the risk of transmission to caregivers and close contacts.
• Be ≥ 18 years of age (or legal age of majority in the jurisdiction) on day of signing informed consent.
• Life expectancy of at least 4 months as determined by the Investigator.
• Patients must be willing to comply with mandatory pre-treatment and on-treatment biopsies.

• Has disease eligible for therapy with curative intent.
• Has had prior treatment with any oncolytic virus
• Has had prior surgery, chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to first dose, or prior anti-cancer monoclonal antibody (mAb) therapy within 45 days prior to study Day 1.
  • Note: Patients are allowed to receive any of the following treatments up to 7 days prior to the first dose:
  • Stereotactic radiosurgery (SRS);
  • Stereotactic body radiation therapy (SBRT); or
  • palliative radiation outside the chest and brain. Irradiated lesions cannot be used as a site for biopsy or TBio-6517 injection.
• Has failed to recover (e.g., to ≤ Grade 1 or to baseline status) from clinically relevant or significant AEs associated with prior cancer treatment.
  • Note: Except patients with ≤ Grade 2 neuropathy or any grade of alopecia.
• Has tumor(s) invading a major vascular structure (e.g., carotid artery) or other key anatomical structure (e.g., pulmonary airway) in the event of post-treatment tumor swelling and/or necrosis.
• Requires use of anti-platelet or anti-coagulant therapy that cannot be safely suspended for per protocol ITu injections or biopsies per standard of care, including the discontinuation of NSAIDs, including ASA, at least 7 days prior to any study biopsy or ITu injection.
• Has CNS metastases that have not been completely resected or completely irradiated and/or carcinomatous meningitis.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) virus infection.
• Has used excluded anti-viral medication (e.g., IFN/peg-IFN, ribavirin, etc.) within 14 days of Day 1 and that cannot be suspended throughout the initial TBio-6517 treatment period and for at least 14 days prior to and after each booster dose of TBio-6517 Note: Acyclovir is permitted.
• Has significant immunodeficiency due to underlying illness (e.g., known HIV/AIDS) or has received systemic immunosuppressive medication including high-dose corticosteroids (e.g., systemic corticosteroids > 10 mg prednisone or equivalent), other than protocol-required pre-medications, within 4 weeks prior to the first dose of trial treatment. Inhaled steroid doses ≤ 10 mg prednisone or equivalent are permitted in the absence of active autoimmune disease.
  • Note: High dose corticosteroids administered for contrast allergy prophylaxis is permitted throughout the trial prior to radiographic scans as long as the first dose of TBio-6517 is at least 7 days after the corticosteroid administration.
• Prior history of myocarditis.
• Given the potential risk of tachycardia, hypotension, and/or fluid volume loading during or following treatment with oncolytic viruses, patients with the following should be excluded:
  • Symptomatic cardiovascular disease, including but not limited to, significant coronary artery disease (e.g., myocardial infarction or other coronary artery disease requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months;
  • Asymptomatic cardiovascular disease (current or past history) unless cardiology consultation and clearance has been obtained for study participation;
  • New York Heart Association functional class III-IV heart failure on active treatment;
  • Patients who for any other reason cannot tolerate tachycardia, hypotension, and/or fluid volume loading.
• Has a known additional malignancy except basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Is pregnant, currently breastfeeding or intending to breastfeed, or expecting/trying to conceive or father children within the projected duration of the trial, starting with Screening through 120 days after the last dose of study treatment including pembrolizumab.
• Pulse oximetry of < 90% in room air at rest.
• Ongoing severe inflammatory skin condition or history of severe eczema requiring prior medical treatment.
• Has had prior organ transplant.
• Has evidence of active, non-infectious pneumonitis.
• Has a history of interstitial lung disease.
• Has an illness, metabolic dysfunction, physical examination finding, or clinical laboratory finding that gives reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug or that would limit compliance with study requirements Has severe atopic disease or known active milk allergy.
• Has received a live vaccine within 30 days of planned study treatment.
• Has a previously identified AVM in an organ where intratumoral injection or tumor biopsy is intended to occur.
• Has known adrenal insufficiency requiring replacement doses of corticosteroids.
• Has received > 4 prior lines of therapy for metastatic or locally advanced disease (neoadjuvant or adjuvant therapy does not count as a prior regimen in this regard).

In addition to above, the following Exclusion Criteria are applicable to patients intending to receive pembrolizumab combination (i.e., Arm B and Arm D):

• Has been intolerant to prior PD-1/PD-L1 targeted antibody therapy for which re-treatment would expose the patient to clinically significant risk in the opinion of the Investigator (please obtain Sponsor permission for enrollment of any patient with prior intolerance to anti-PD1/PD-L1 antibody treatment).
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immune-modulating drugs). Replacement therapy with thyroxine or insulinis not considered an excluded form of systemic treatment.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.

• Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent according to federal, local, and institutional guidelines prior to initiation of any study-specific procedure.
• At least 18 years old at screening.
• Body weight > 45 kg at screening.
• Adequate acoustic windows to enable accurate TTE (refer to the central echocardiography laboratory’s manual of operations).
• Diagnosed with oHCM (unexplained LV hypertrophy with nondilated ventricular chambers in the absence of other cardiac [e.g., aortic stenosis, hypertension]) or systemic disease. Patient has maximal septal wall thickness ≥ 15 mm or ≥ 13 mm with family history of HCM consistent with current ACCF/AHA 2011 and/or ESC 2014 guidelines (per the country in which the site is located). Patient must meet ACCF/AHA 2011 and/or ESC 2014 guideline recommendations for invasive SRT therapies as follows:
  • Clinical criteria: Despite maximally tolerated drug therapy severe dyspnea or chest pain (NYHA Class III or IV) or for the purposes of the Valor Study, subjects who are NYHA Class II with exertion-induced syncope or near syncope;
  • Hemodynamic criteria: dynamic LVOT gradient at rest or with provocation (i.e., Valsalva or exercise) ≥ 50 mmHg associated with septal hypertrophy (read by the core echocardiography laboratory);
  • Anatomic criteria: targeted anterior septal thickness sufficient to perform the procedure safely and effectively in the judgment of the individual operator.
• Referred or under active consideration within the past 12 months for SRT procedure and willing to have SRT procedure.
• Subjects referred or considered for ASA must have an adequate first septal perforating branch of left anterior descending (LAD) coronary artery, amenable for the interventionalist to perform the procedure.
• Documented oxygen saturation at rest ≥ 90% at screening.
• Documented LVEF ≥ 60% at screening according to core echocardiography laboratory reading.
• Female subjects not pregnant or lactating and, if sexually active, must either practice true abstinence or use 1 of the following highly effective birth control methods from screening through 3 months after the last dose of study drug:
  • Estrogen- and progestogen-containing hormonal contraception associated with inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation by oral, implantable, or injectable route of administration;
  • Intrauterine device;
  • Intrauterine hormone-releasing system;
  • Bilateral tubal occlusion;
  • Female surgically sterile or postmenopausal for 1 year. Permanent sterilization includes hysterectomy, bilateral oophorectomy, bilateral salpingectomy, and/or documented bilateral tubal occlusion. Females are considered postmenopausal if they have had amenorrhea for ≥1 year after cessation of all exogenous hormonal treatments, and follicle stimulating hormone (FSH) levels are in the postmenopausal range.
• Male partners of female subjects must also use a contraceptive (e.g., barrier, condom, or vasectomy) from screening through 4 months after the last dose of study drug.

• Previously participated in a clinical study with mavacamten (individuals who failed screening for a prior mavacamten study may participate).
• Hypersensitivity to any of the components of the mavacamten formulation.
• Participated in a clinical trial in which the subject received any investigational drug (or currently using an investigational device) within 30 days prior to screening, or at least 5 times the respective elimination half-life (whichever is longer).
• Known infiltrative or storage disorder causing cardiac hypertrophy that mimics oHCM, such as Fabry disease, amyloidosis, or Noonan syndrome with LV hypertrophy.
• Planned invasive procedure during the first 32 weeks of the study.
• Papillary muscle or mitral valve in need of repair or any other intracardiac procedure planned (however, if need for mitral valve repair is discovered during SRT procedure, the subject will continue to be followed on study).
• For individuals on beta blockers, calcium channel blockers, or disopyramide, any dose adjustment of these medications < 14 days prior to screening or an anticipated change in regimen during the first 16 weeks of the study.
• Any medical condition that precludes upright exercise stress testing.
• Paroxysmal, intermittent atrial fibrillation with atrial fibrillation present at screening per the investigator’s evaluation of the subject’s electrocardiogram (ECG).
• Persistent or permanent atrial fibrillation and subject not on anticoagulation for ≥ 4 weeks prior to screening and/or not adequately rate controlled ≤ 6 months prior to screening.
• Previously treated with invasive septal reduction (surgical myectomy or percutaneous ASA). However, if the participant has a history of a suboptimal or a failed alcohol septal ablation and there is no evidence on site read prescreening echocardiogram of an ASA, the participant may be included after consultation with the MyoKardia or CRO medical monitor.
• Planned ICD placement or pulse generator change during the first 32 weeks of the study.
• ECG abnormality considered by the investigator to pose a risk to participant safety (eg, second degree atrioventricular block type II).
• Acute or serious comorbid condition (eg, major infection or hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction) that in the judgment of the investigator could lead to premature termination of study participation or interfere with the measurement or interpretation of the efficacy and safety assessments in the study:
  • Pulmonary disease that limits exercise capacity or systemic arterial oxygen saturation;
  • History of malignant disease within 10 years prior to screening:
    • Subjects who have been successfully treated for nonmetastatic cutaneous squamous cell or basal cell carcinoma or have been adequately treated for cervical carcinoma in situ or breast ductal carcinoma in situ may be included in the study;
    • Subjects with other malignancies who are cancer-free for more than 10 years prior to screening may be included in the study.
• History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to subject safety or interfere with study evaluations, procedures, or completion.
• Safety laboratory parameters (chemistry, hematology, coagulation, and urinalysis) outside normal limits (according to the central laboratory reference range) at screening as assessed by the central laboratory; however, a subject with safety laboratory parameters outside the normal limits may be included if all the following criteria are met:
  • Safety laboratory parameters outside normal limits are considered by the investigator to be clinically not significant;
  • If an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) result, the value must be < 3 × the upper limit of the laboratory reference range;
  • Body size–adjusted estimated glomerular filtration rate is ≥ 30 mL/min/1.73 m^2.
• Has known moderate or severe aortic valve stenosis or moderate to severe aortic stenosis determined at screening (as read by the echocardiography core laboratory).
• Positive serologic test at screening for infection with human immunodeficiency virus (HIV); hepatitis C virus (HCV); or hepatitis B virus (HBV), with the exception of HBV s-antibody positive which is a marker of immunity.
• Known active infection with Covid-19 (PCR+) within 90 days of screening. If subject had a PCR+ test within 6 months of screening, they must have a negative Covid-19 test at screening.
• Prior treatment with cardiotoxic agents, such as doxorubicin or similar.
• Unable to comply with the study requirements, including the number of required visits to the study site.
• First-degree relative of personnel directly affiliated with the study at the study site, any study vendor, or the study sponsor.

Eligibility last updated 10/14/21. Questions regarding updates should be directed to the study team contact.

• All races, ethnicities and genders are eligible for enrollment in this study. 
• Subjects must be aged 22-65 years old. 

Additional inclusion criteria are: 

• Provision of signed and dated informed consent.
• Subject must be agreeable and compliant with study requirements, including the three (baseline, 2 month, and 6 month) visits, as well as undergoing GEBT and NSSM testing.
• If female, must be post-menopausal, surgically sterile, or agree to practice birth control during year of study and have negative serum HCG at screening/baseline.
• Must be willing and able to travel, as needed, to the Investigator’s office to complete all routine follow-up visits.

Patients presenting any of the following conditions, or meeting any of the criteria below, are to be excluded from enrollment: 

• Persons presently or soon to be incarcerated.
• Females who are pregnant or suspect they may be pregnant.
• Persons with nicotine and/or alcohol dependence.
• Patients with cognitive impairment that limits their ability to make autonomous decisions. 
• Known allergies or sensitivities to study materials (eggs and spirulina).
• Assessed, by the physician or delegate, that enrollment would not be appropriate.

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

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

• Adult and pediatric patients will be considered eligible for accrual.
• Pediatric patients (Age < 18 years) must weigh ≥ 10 kg for consideration.
• Diagnosis of previously untreated or progressive sarcoma who will receive systemic chemotherapy.
• Willing and able to provide written informed consent and age appropriate assent for minors.
• Planned clinical biopsy/surgery or available archived tumor tissue.

• Pediatric sarcoma patients weighing < 10 kg.
• Unable/unwilling to provide written informed consent.

Eligibility last updated 1/13/22. Questions regarding updates should be directed to the study team contact.

• Urine protein to creatinine ratio of ≥ 3.0 g/g (as measured from a 24 hour urine collection).
• Active anti-PLA2R antibody positive MN in need for immunosuppressive therapy (IST) according to investigator judgement and diagnosed on the basis of a biopsy, archival biopsy acquired within 5 years prior to screening is acceptable.
• Estimated glomerular filtration rate ≥ 50 ml/min/1.73m² or >30 and < 50 ml/min/1.73m², and interstitial fibrosis and tubular atrophy score of less than 25% on a renal biopsy obtained within the last 6 months prior to start of screening.
• on supportive treatment with an Angiotensin Converting Enzyme Inhibitor or an Angiotensin II Receptor Blocker for at least 4 weeks prior to Screening, having reached a stable dose.
• Systolic BP ≤ 150 mmHg and diastolic BP ≤ 100 mmHg -Vaccinated against Pneumococcus within the last 3 years prior to date of signing informed consent (subjects may be vaccinated during screening to meet this criterion; interval to first dose of MOR202 must be at least 14 days).
• Cohort 1a (newly diagnosed patients):
  • Serum anti-PLA2R antibodies ≥ 150.0 Response Units(RU)/mL determined at screening by Euroimmun ELISA.
• Cohort 1b, relapse subjects:
  • Must have had complete immunological and/or clinical remission according to judgement of the investigator and serum anti-PLA2R antibodies ≥ 50.0 RU/mL determined at screening by Euroimmun ELISA.
• Cohort 2:
  • Failure of previous therapy; i.e., subject never achieved a complete immunological and/or clinical remission according to judgement of the investigator. during or after completion of a recognized IST containing cyclosporine A, tacrolimus, mycophenolate-mofetil, ACTH or alkylating agents (e.g., cyclophosphamide), or rituximab. Serum anti-PLA2R antibodies ≥ 20.0 RU/mL determined at screening by the Euroimmun ELISA.

• Hemoglobin < 90 g/L.
• Thrombocytopenia: Platelets < 100.0x10^9/L.
• Neutropenia: Neutrophils < 1.5x10^9/L.
• Leukopenia: Leukocytes < 3.0x10^9/L.
• Hypogammaglobulinemia: Serum immunoglobulins ≤ 5.0 g/L.
• Secondary cause of MN (e.g., Systemic lupus erythematosus, medications, malignancies). 
• Concomitant renal disease other than MN (e.g., diabetic renal disease, lupus nephritis, IgA nephropathy).

• Male or female, between 18 and 65 years of age (inclusive) at the time of Screening.
• Female subjects must:
  • not be pregnant, lactating, or breastfeeding;
  • be either postmenopausal (defined as amenorrhea for ≥ 12 months), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy), or if of child-bearing potential (WOCBP) must agree to practice appropriate methods of birth control or remain abstinent during the study and for 30 days after the last dose of study drug;
  • Acceptable forms of contraception include any of the following:
  • oral contraceptives;
  • double barrier methods of non-hormonal contraception are permitted in this study:
  • female condom with spermicide (cream, spray, gel, suppository, contraceptive sponge, or polymer film)
  • diaphragm with spermicide (with or without a condom)
  • cervical cap with spermicide (with or without a condom)
  • male sexual partner who agrees to use a male condom in addition to female subject’s use of spermicide (cream, spray, gel, suppository, contraceptive
  • other explanation for the ALT elevations and the agreement of the medical monitor and sponsor.
  • Permanent discontinuation of prior tolvaptan treatment because of the abnormal liver chemistry test results.
  • If re-challenge with tolvaptan was performed, the ALT level should have increased to >2 x ULN upon re-challenge or the ALT level was increasing but tolvaptan was stopped for patient safety reasons before it reached > 2 x ULN after having previously normalized.
  • Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the subject) without the use of a diuretic in concert with KDIGO “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease”.
  • Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study- related procedures.

• Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds.
• Hypovolemia or inability to perceive thirst.
• Subjects who are taking, have taken within the past 2 weeks, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John's wort.
• Prior use of tolvaptan within the past 3 months or until a previously elevated ALT level has returned to ≤ 1 x ULN.
• Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, venglustat, demeclocycline, or mammalian Target of Rapamycin (mTOR) kinase inhibitors (e.g., everolimus, sirolimus, etc.) to treat ADPKD within the past 3 months.
• Requirement for chronic diuretic use.
• Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] > 7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant renal disease, transplanted kidney, recent kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within past 6 months.
• Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
• New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the subject.
• Clinically significant liver disease or impairment or active chronic hepatitis at Screening.
• Elevated baseline levels of serum ALT or total bilirubin.
• History of drug or alcohol abuse in the past 2 years.

• Male or female and at least 18 years of age at screening.
• Has a history of UC for at least 3 months prior to screening (with involvement beyond the rectum to at least 15 cm from the anal verge).
• Has moderate-to-severely active UC, as defined by a Mayo endoscopic subscore of ≥ 2 points and an adapted Mayo score between 4
  •9 points, inclusive.
• Is corticosteroid-dependent or has demonstrated inadequate response, or intolerance to conventional therapy (aminosalicylates, corticosteroids, immunomodulators) or biologics.
• If subject is currently receiving oral aminosalicylate (e.g., mesalamine products, balsalazide, or sulfasalazine):
• Subject is eligible provided the subject has been on it at a stable dose for ≥ 4 weeks prior to Day 1.
• During the Study and for 7 days after receiving the last dose of the Study drug, females of childbearing potential or men capable of fathering children must agree to use highly effective birth control measures (failure rate < 1% when used consistently and correctly) or agree to abstain from sexual intercourse. Females of childbearing potential must test negative for pregnancy at screening and at Day 1.
• All male subjects must agree to refrain from semen donation during the Study and for 7 days after the last dose of Study drug.
• Must be able and willing to adhere to the Study visit schedule and comply with other protocol requirements.
• Are capable of providing informed consent, which must be obtained prior to any Study-related procedures.

Inclusion Criteria for Extended Induction (additional 8 weeks):

• Did not meet criteria for clinical response by adapted Mayo score using centrally read endoscopic subscore at Week 8a.

Inclusion Criteria for Maintenance Study:

• Must have met the criteria for a clinical response by adapted Mayo score using centrally read endoscopic subscore during Induction at Week 8a or during Extended Induction Study at Week 16.

• Has symptoms suggestive of fulminant colitis, megacolon or intestinal perforation.
• Has primary sclerosing cholangitis (PSC).
• Likely to require surgery for UC or other major surgeries.
• Has had a clinically significant, as deemed by the investigator, prior intestinal resection for UC or for other gastrointestinal diseases (e.g., that may have resulted in chronic diarrhea)
• Has previously received / is currently receiving prohibited medications within specified timeframe.
• Is refractory to 3 biologics with ≥ 2 mechanisms of action.
• Has a current bacterial, parasitic, fungal, or viral infection.
• Has clinically significant abnormalities in laboratory evaluations.
• Has had any prior exposure to an approved Janus kinase (JAK) inhibitor or potential exposure to an investigational JAK inhibitor that was stopped due to intolerance or lack of efficacy.
• Are pregnant, lactating, breastfeeding or planning to become pregnant during the Study or within 7 days after the last dose of Study Drug.
• Has known moderate or severe hepatic impairment (e.g., Child-Pugh Class B or C).
• Has clinically significant abnormalities in the results of laboratory evaluations at screening visit as determined by the investigator, including:
  • AST, ALT, or alkaline phosphatase ≥ 2 x the upper limit of normal (ULN);
  • Total bilirubin > 2 x ULN (unless diagnosis of Gilbert’s syndrome);
  • Creatinine clearance as calculated by the Cockcroft-Gault formula < 30 mL/min;
  • Total white blood cell count (WBC) < 3 x 10^9 /L;
  • Absolute neutrophil count < 1.5 x 10^9 /L;
  • Absolute lymphocyte count < 0.8 x 10^9 /L;
  • Hemoglobin < 8 g/dL; or
  • Platelet count < 100 x 10^9 /L.
• Has a clinically significant abnormal electrocardiogram (ECG) at screening, including QTcF > 450 msec for males and > 470 msec for females.
• Has unstable or uncontrolled and clinically significant condition/disease that would compromise subject safety or confound Study safety assessment as determined by the investigator at screening and Day 1.
• Has known hypersensitivity to excipients or contents of the Study drug.
• Has participated in another clinical trial of an investigational drug (or medical device) within 30 days prior to Screening or 5 x the half-life of the investigational drug, whichever is longer, or is currently participating in another trial of an investigational drug (or medical device).
• Have or has a history of alcohol or drug abuse within 1 year of screening, per the judgment of the investigator.
• Has a current, or history of, malignancy requiring radiation or pharmacologic treatment within 5 years prior to screening, except for completely resected basal cell carcinoma or squamous cell carcinoma of the skin without recurrence for ≥ 1 year, cervical carcinoma in situ that has been adequately treated and without recurrence for ≥ 5 years.
• Is deemed by the investigator to be inappropriate for this Study; or has any condition which would confound or interfere with the evaluation of the safety, tolerability, or PK of the investigational drug; or is unable or unwilling to comply with the Study protocol.

• Adolescent Idiopathic Scoliosis classified as Lenke Type 1 or Type 5 curves.
• Cobb angle between 40-60 degrees (inclusive).
• Flexible curve that that reduces to ≤ 30 degrees on lateral side bending radiographs or as evident by traction x-ray.
• Kyphosis angles of ≤ 55 degrees measured from T5 to T12.
• Appropriate candidate for posterior surgical approach.
• Patient has good general health.
• Patient has no known hypersensitivity or allergies to titanium.
• Patient’s guardian signs a written informed consent form (ICF).

• Any type of non-idiopathic scoliosis.
• Any main thoracic deformity that includes vertebral levels and cranial including to T2.
• Known history of existing malignancy, or any systemic or local infection.
• Spinal cord abnormalities that require treatment.
• Known neurological deficit (defined as motor grade < 5/5).
• Known poor bone quality defined as T score -1.5 or less.
• For female patient, pregnancy.
• Previous spine surgery.
• Active systemic disease, such as AIDS, HIV, or active infection.
• Active infection or the skin is compromised at the surgical site.
• Systemic disease that would affect the Patient’s welfare or overall outcome of the study.

• Adolescent Idiopathic Scoliosis classified as Lenke Type 1 or Type 5 curves.
• Cobb angle between 40-60 degrees (inclusive).
• Flexible curve that that reduces to ≤ 30 degrees on lateral side bending radiographs or as evident by traction x-ray.
• Kyphosis angles of ≤ 55 degrees measured from T5 to T12.
• Appropriate candidate for posterior surgical approach.
• Patient has good general health.
• Patient has no known hypersensitivity or allergies to titanium.
• Patient’s guardian signs a written informed consent form (ICF).

• Any type of non-idiopathic scoliosis.
• Any main thoracic deformity that includes vertebral levels and cranial including to T2.
• Known history of existing malignancy, or any systemic or local infection.
• Spinal cord abnormalities that require treatment.
• Known neurological deficit (defined as motor grade < 5/5).
• Known poor bone quality defined as T score -1.5 or less.
• For female patient, pregnancy.
• Previous spine surgery.
• Active systemic disease, such as AIDS, HIV, or active infection.
• Active infection or the skin is compromised at the surgical site.
• Systemic disease that would affect the Patient’s welfare or overall outcome of the study.

• Undergoing treatment, or have undergone treatment, for cancer at a Mayo Clinic Midwest medical oncology clinic.

• Lack of English fluency.
• Membership in a vulnerable population
  •prisoner.
• Membership in a vulnerable population
  •mentally handicapped.
• Membership in a vulnerable population
  •Axis I psychiatric condition.

• Patient 18 years or older with breast cancer and biopsy-proven malignant involvement of an axillary lymph node
• Patient is not pregnant.
• Surgical management involves preoperative radioactive seed localization of a previously identified positive axillary lymph node
• Surgery will be performed by Dr. James Jakub.
• Radioactive seed localization is scheduled at least one day prior to surgery.
• No contraception is necessary or required.
• English speaking

• Age 21-75 years old, inclusive.
• Pain and discomfort of unknown etiology between the costal margins and inferior gluteal folds with or without referred pain to the lower limbs), lasting for more than 12 weeks (measured by patient past history and lumbar physical exam).
• There may be waist muscle weakness, stiffness, limited mobility or reduced spinal coordination. The symptoms of pain are lessened or disappeared after bed rest. While the symptoms of pain are aggravated after bending over, sedentary, or standing for a long time (measured by patient past history and lumbar physical exam).
• Physical examination showed an increase in muscle tension or a significant localized tenderness point (trigger point) in the painful area, with negative straight-leg raising test, and no signs of nerve root lesions.
• Patients with Radiographic results of MRI, CT and X-ray within 1 year.
• Female patients who are of childbearing potential and are likely to become pregnant during the treatment phrase must have a negative pregnancy test (human chorionic gonadotropin (HCG) urine test).

• Patients with low back pain associated with nerve root compromise (measured by clinical examination of dermatomes, myotomes and reflexes).
• Patients with severe skin diseases (e.g., skin cancer, erysipelas, severe eczema, severe dermatitis, severe psoriasis and severe hives lupus) (measured by patient past history and lumbar physical exam).
• Serious spinal pathologies such as fractures, tumors, inflammatory and infectious diseases (measured by patient past history and lumbar physical exam).
• History of lumbar spinal surgery (measured by patient past history).
• Serious cardiovascular or metabolic disorders, such as heart failure, severe osteoporosis (measured by patient past history).
• Patients diagnosed with cognitive issues such as major depression, and moderate to severe dementia severe psychiatric diseases (such as schizophrenia, bipolar affective disorder, paranoid psychosis) (measured by patient past history).
• Women who are pregnant, or who are of childbearing potential and are likely to become pregnant during the treatment phase but are not willing to use a reliable form of contraception.  Reliable forms of contraception include oral contraception, diaphragm or condom (with spermicide), injections, intrauterine device, surgical sterilization, and abstinence.

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

• Cohort 1 Inclusion: 

• Mayo Clinic patients known or suspected to be positive with COVID-19 and/or infection with SARS-CoV-2.
• Hospitalized at time of identification.
• All ages will be eligible with appropriate controls for pediatric patients.
• All racial and ethnic groups are eligible. 
   
  Cohort 2 Inclusion:
• Mayo Clinic patients known or suspected to be positive with COVID-19 and/or infection with SARS-CoV-2.
• Not hospitalized at time of identification.
• All racial and ethnic groups are eligible. 

• None.

• Mayo Clinic patients diagnosed with or suspected to have COVID-19 (infection with SARS-CoV-2).

• None.

• Pregnant females age 18-45 years and their infants.
• Willing and able to provide written informed consent.
• Pregnant and planning to deliver at Mayo Clinic.

• Positive for HIV, HBV or TB.
• Delivery not planned at Mayo Clinic.
   

For Dose Escalation

• Have a histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable and for whom there is no available standard therapy.

For Expansion

• Have histologically or cytological confirmed diagnosis of relapsed or refractory, advanced and/or metastatic NSCLC, EC, UC, TNBC, SCCHN, or cervical cancer who are not anymore candidates for standard therapy.

For Both Dose Escalation and Expansion

• Have measurable disease according to RECIST 1.1.
• Have Eastern Cooperative Oncology Group (ECOG) 0-1.
• Have an acceptable hematological status.
• Have acceptable liver function.
• Have an acceptable coagulation status.
• Have acceptable renal function.

• • Ongoing or active infection requiring intravenous treatment with antiinfective therapy;
  • Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris or cardiac arrhythmia;
  • Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg, despite optimal medical management;
  • Ongoing or recent evidence of autoimmune disease;
  • History of irAEs that led to prior checkpoint treatment discontinuation;
  • Prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade;
  • History of chronic liver disease or evidence of hepatic cirrhosis;
  • History of non-infectious pneumonitis that has required steroids or currently has pneumonitis;
  • History of organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of GEN1046;
  • Serious, non-healing wound, skin ulcer (of any grade), or bone fracture.
• Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger than 6 months) or progressive brain metastases or stroke.
• Prior therapy:
  • Radiotherapy: Radiotherapy within 14 days prior to first GEN1046 administration. Palliative radiotherapy will be allowed;
  • Treatment with an anti-cancer agent (within 28 days or after at least 5 half-lives of the drug, whichever is shorter), prior to GEN1046 administration. Accepted exceptions are bisphosphonates (e.g., pamidronate, zoledronic acid, etc.) and denosumab.
• Toxicities from previous anti-cancer therapies that have not adequately resolved.

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

Inclusion Criteria
•COVID Patient:

• Adults, age ≥ 18 years old.
• Confirmed history of COVID-19 viral infection.
• Now clinically recovered.
• COVID-19 negative on re-testing or if COVID test is not available, must be symptom-free for 2 weeks.

Exclusion Criteria
•COVID Patient:

• Post-recovery COVID-19 virus testing remains positive.

Inclusion Criteria 
•Healthy Volunteer:

• Otherwise healthy adults (age ≥ 18).
• Not acutely ill.

Inculsion Criteria

1. High risk critically ill patients: adults (age ≥18) in acute respiratory failure and/or requiring vasopressors admitted to the ICU and expected to stay >48 hours. adults (age ≥18) in acute respiratory failure and/or requiring vasopressors admitted to the ICU and expected to stay >48 hours
2. Enrolled patient’s family members.
3. Critical care nurses.
4. Physical/Occupational therapists writing ICU diary entries.

1. History of dementia, mental retardation, suicide attempt, psychotic disorders such as schizophrenia, acute alcohol/substance intoxication or withdrawal, severe metabolic encephalopathy; patients on comfort care; patients not expected to survive the hospital stay or non-English speaking

• Provide written informed consent.
• Age ≥ 18 years old.
• Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability (MSI)/mismatch repair (MMR) status must be documented, according to country guidelines.
• Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agent and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with:
  • standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy;
  • an anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab). [Please note that regorafenib is NOT an anti-VEGF biologic]; and
  • if RAS wild-type, an anti-EGFR therapy (e.g., cetuximab, panitumumab);
• Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject’s country unless the subject is ineligible for treatment with a checkpoint inhibitor.
• Subjects who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Subjects who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible.
• Body weight ≥ 40kg.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions.
• Expected survival > 12 weeks.
• For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (< 1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (e.g., diaphragm, with a spermacide).The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
• Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject’s country unless the patient is ineligible for treatment with a BRAF inhibitor.

• Absolute neutrophil count (ANC) < 1.5×10^9/L.
• Platelet count < 100 × 10^9/L.
• Hemoglobin < 9.0 g/dL.
• Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed.
• Serum total bilirubin > 1.5 × the upper limit of normal (ULN).
• ALT or AST > 2.5 × ULN in subjects without hepatic metastases; ALT or AST > 5 × ULN in subjects with hepatic metastases.
• Serum creatinine > 1.5 × ULN or creatinine clearance < 60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation.
• Urine dipstick or urinalysis with protein ≥ 2+ or 24-hour urine protei ≥ 1.0 g/24-h. Subjects with greater than 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level. 
• Uncontrolled hypertension, defined as: systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mm Hg despite optimal medical management. The subject must have blood pressures below both limits. Repeated assessments are permitted.
• International Normalized Ratio (INR) > 1.5 x ULN or activated partial thromboplastin time (aPTT) > 1.5 × ULN, unless the subject is currently receiving or intended to receive anticoagulants for prophylactic purposes.
• History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening.
• History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening.
• History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
• Stroke and/or transient ischemic attack within 12 months prior to screening;
• Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) 480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
• Concomitant medications with a known risk of causing QT prolongation and/or torsades de pointes (Source list is continuously updated online at www.crediblemeds.org).
• Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy.
• Systemic small molecule targeted therapies (e.g., tyrosine kinase inhibitors) within 5 halflives or 4 weeks (whichever is shorter) prior to the first dose of study drug.
• Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug.
• Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug;
• Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug.
• Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision.
• Any unresolved toxicities from a previous antitumor treatment greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) v5.0 grade 1 (except for alopecia or neurotoxicity grade ≤ 2).
• Known human immunodeficiency virus (HIV) infection.
• Known history of active viral hepatitis. For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Subjects with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• Clinically uncontrolled active infection requiring IV antibiotics.
• Tumor invasion of a large vascular structure (eg, pulmonary artery, superior or inferior vena cava).
• Women who are pregnant or lactating.
• Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; subjects requiring steroids within 4 weeks prior to start of study treatment are excluded.
• Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening.
• Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (e.g., gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product.
• Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the subject at undue risk of harm based on the investigator’s assessment.
• Known hypersensitivity to fruquintinib or any of its (or placebo) inactive ingredients including the azo dyes Tartrazine
  •FD&C Yellow 5 and Sunset yellow FCF
  •FD&C Yellow 6.
• Subjects who have received prior fruquintinib.
• Live vaccine ≤ 28 days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

Eligibility last updated 10/1/21. Questions regarding updates should be directed to the study team contact.