1. Willing and able to provide written informed consent
2. Age ≥ 18 years
3. Diagnostic coronary angiography/left heart catheterization or percutaneous coronary intervention via the transradial approach

1. Presence of a palpable hematoma or clinical concern of hemostasis at the transradial access site in which bleeding risk would be prohibitive
2. Access or attempted access site – including contralateral radial artery, brachial artery, or femoral artery or vein as switching of access could be attributed to arterial injury
3. Planned staged procedure, coronary artery bypass grafting or noncardiac surgery, within 30 days
4. Pregnant or lactating females
5. Contraindication or high risk of bleeding with anticoagulation
   1. bleeding requiring medical attention in the previous 6 months
   2. thrombocytopenia (platelets < 50 x 10^9/L)
   3. any prior intracranial hemorrhage
   4. use of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention
   5. administration of thrombolytic therapy in the preceding 24 hours
   6. use of regular non-steroidal anti-inflammatory medications excluding Aspirin < 100mg/day
   7. ischemic stroke or transient ischemic attack diagnosed in the last 3 months
6. Cardiogenic shock
7. Ventricular arrhythmias refractory to treatment
8. Liver dysfunction (Child-Pugh class B or C)
9. Unexplained anemia with a Hgb below 100 g/L
10. History of medication noncompliance or risk factor for noncompliance
11. Active malignancy
12. Allergy to rivaroxaban
13. Another indication for anticoagulation
14. Strong CYP3A4 and P-glycoprotein inhibitor use which increase rivaroxaban levels (ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, diltiazem, verapamil and conivaptan, carbamazepine, phenytoin, rifampin, St.John’s wort)
15. Life expectancy <30 days
16. Women capable of pregnancy not on birth control
17. Chronic kidney disease with creatinine clearance of less than 30mL/min
18. History of antiphospholipid syndrome, in particular triple positive (lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies)

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

Eligibility last updated 8/22/23. Questions regarding updates should be directed to the study team contact.

• Provision of signed and dated informed consent form.
• Subject is 18 years of age and older.
• Subject has a diagnosis of unresectable Stage 3 pancreatic adenocarcinoma cancer cytologically or pathologically confirmed per American Joint Committee on Cancer (AJCC) staging criteria.
• Subject has a tumor evaluated as Stage 3 according to National Comprehensive Cancer Network (NCCN) guidelines, based on radiographic imaging or exploratory surgery.
• Maximum axial and anterior to posterior tumor dimension of ≤3.5cm, after receiving three months of treatment with the modified FOLFIRINOX regimen.
• Subject has received 3 months of treatment with the modified FOLFIRINOX regimen.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Subject has an American Society of Anesthesiologists (ASA) classification of physical health status of 1, 2, 3 or 4.

• Subjects who are or may be pregnant as determined by a positive pregnancy test or breastfeeding or male or female patients of reproductive potential who are not willing to employ highly effective birth control from screening to 6 months after the last dose of chemotherapy.
• Subjects who are unable to tolerate general anesthetic with full skeletal muscle blockade.
• Subjects who are actively bleeding, anticoagulated, coagulopathy, or have any of the following hematology results:
  • hemoglobin less than 10 g/dL without the support of growth factors or transfusion; absolute neutrophil count less than 1500 cells/mL; or
  • platelet count less than 100,000.
• Subjects with the presence of implanted cardiac pacemakers, defibrillators, electronic devices or implanted devices with metal parts in the thoracic cavity at the time of IRE.
• Subjects with history of epilepsy or other neurological disease.
• Subjects with renal, cardiac, liver, or hematological abnormalities of concern to the investigator.
• Subjects with Stage 3, 4, or 5 chronic kidney disease.
• Subjects receiving IRE for margin accentuation.
• Subjects who at 3 months after FOLFIRINOX treatment have evidence of disease progression.
• Participation in another interventional trial for pancreatic cancer.
• Subjects who did not meet study defined criteria for adequacy of induction treatment at the end of the 3 months.

• The subject’s Legally Authorized Representative (LAR) provides written informed consent, approved by the appropriate Institutional/Independent Review Board and is able to comply with study requirements and visit schedule.
• Is 0-3 years of age.
• Has a cataract and is expected to undergo cataract surgery with or without implantation of a posterior chamber intraocular lens.
• To be eligible for participation, subjects must undergo primary cataract surgery.

• Any intraocular inflammation in the study eye.
• Over 3 years of age.
• Ocular hypertension or glaucoma.
• Evidence of acute external ocular infections.

• Symptomatic, moderate-to-severe or severe mitral regurgitation (MR ≥ Grade III per American Society of Echocardiography criteria), or severe mitral annular calcification (MAC), where a transcatheter therapy is deemed more appropriate than conventional mitral valve surgery by the local site heart team.
  • Note: MR severity must be determined by assessment of a qualifying transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE), obtained within 120 days prior to subject consent, and must be confirmed by the Echocardiography Core Laboratory.
  • Note: Patients with severe MAC must have symptomatic mitral valve disease associated with MR ≥ Grade III, or severe mitral stenosis (MS), or both moderate MR and moderate MS as assessed by the Echocardiography Core Laboratory.
• NYHA Functional Classification ≥ II (if Class IV, patient must be ambulatory).
• The local site heart team determines that the subject has been adequately treated per applicable standards for coronary artery disease (e.g., revascularization), left ventricular dysfunction (e.g., cardiac resynchronization therapy) and heart failure (e.g., GDMT). The Subject Eligibility Committee must concur that the subject has been adequately treated.
• The local site heart team and the Subject Eligibility Committee concur on the intended study cohort for the subject.
  • Randomized Cohort: Eligibility for this cohort is limited to subjects where the local site heart team deems the mitral valve anatomy is amenable to transcatheter edge-to-edge repair within approved MitraClip indications. Subjects with primary MR must be at prohibitive surgical risk, while subjects with secondary MR must be symptomatic despite maximally-tolerated guideline- directed medical therapy.
  • Non-repairable Cohort: Eligibility for this cohort is limited to subjects where the local site heart team deems the mitral valve anatomy is not amenable for transcatheter repair with MitraClip or does not meet MitraClip indications.
  • Severe MAC Cohort: Eligibility for this cohort is limited to subjects where the local site heart team deems the degree of MAC renders the subject unsuitable for mitral valve surgery.
• Age 18 years or older at time of consent.
• Subject has been informed of the nature of the trial and agrees to its provisions, including the possibility of randomization to the Control group, complying with trial required testing, medications, and follow-up visits, and has provided written informed consent.

• Mitral valvular vegetation or mass.
• Left Ventricle (LV) or Left Atrium (LA) thrombus.
• Chest condition that prevents transapical access.
• Left Ventricular Ejection Fraction (LVEF) less than 25% assessed by the site based on a TTE obtained within 120 days prior to subject consent.
  • Note: LVEF will be principally based on TTE and must be confirmed by the Echocardiography Core Laboratory.
• Left Ventricular End Diastolic Diameter (LVEDD) > 7.0 cm assessed by the site based on a TTE obtained within 120 days prior to subject consent.
  • Note: A qualifying LVEDD must be confirmed by the Echocardiography Core Laboratory.
• Prior surgical or interventional treatment of mitral valve involving implantation of prosthetic material (e.g. valve repair or replacement, or MitraClip).
• Mitral pathoanatomy and Left Ventricular Outflow Tract (LVOT) anatomy deemed not suitable for Tendyne mitral valve implantation.
• Aortic valve disease requiring surgery or transcatheter intervention.
• Tricuspid valve disease requiring surgery or transcatheter intervention.
• Severe tricuspid regurgitation or severe right ventricular dysfunction.
• Any surgical or interventional procedure within the period of 60 days prior to or planned procedure 60 days following subject registration.
• Implant or revision of Cardiac Resynchronization Therapy (CRT) device within 90 days prior to intended subject registration.
• Myocardial Infarction (MI) within 30 days prior to intended subject registration.
• Symptomatic, unresolved multi-vessel or unprotected left main coronary artery disease (e.g., active ischemia) requiring stenting or Coronary Artery Bypass Grafting (CABG).
• Cerebrovascular accident (CVA) within 6 months prior to intended subject registration.
• Unresolved severe symptomatic carotid stenosis (> 70% by ultrasound).
• Cardiogenic shock or hemodynamic instability requiring inotropes or mechanical support devices at the time of planned implant procedure.
• Hypertrophic or restrictive cardiomyopathy, or constrictive pericarditis.
• Any of the following: leukopenia, acute anemia, thrombocytopenia, history of bleeding diathesis, or coagulopathy if cannot be adequately treated.
• History of endocarditis within 6 months of planned implant procedure.
• Active systemic infection requiring antibiotic therapy.
• Known hypersensitivity or contraindication to procedural or post- procedural medications (e.g., contrast solution, anti-coagulation and antiplatelet therapy) that cannot be adequately managed medically.
• Subjects in whom TEE is contraindicated or high risk.
• Known hypersensitivity to nickel or titanium.
• Subject is undergoing hemodialysis due to chronic renal failure.
• Subject has pulmonary arterial hypertension (fixed PAS > 70mmHg).
  • Note: If PAS > 70mmHg, site must provide documentation PAS is not fixed in order to be eligible.
• Subject has Chronic Obstructive Pulmonary Disease (COPD) requiring continuous home oxygen therapy or chronic outpatient oral steroid use.
• Subjects with non-cardiac comorbidities that are likely to result in a life expectancy of less than 12 months.
• Modified Rankin Scale ≥ 4 disability.
• Status 1 heart transplant or prior orthotopic heart transplantation.
• Pregnant, lactating, or planning pregnancy during the clinical investigation follow-up period.
  • Note: Female subjects of childbearing age should be instructed to use safe contraception (e.g. intrauterine devices, hormonal contraceptives: contraceptive pills, implants, transdermal patches hormonal vaginal devices, injections with prolonged release).
• Currently participating in an investigational drug or another device trial that has not reached its primary endpoint.
  • Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials.
• Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical investigation or to comply with follow- up requirements, or impact the scientific soundness of the clinical investigation results.

Eligibility last updated 4/28/22. Questions regarding updates should be directed to the study team contact.

• Capable of giving signed informed consent including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. For participants <18 years of age (or the legal minimum age in the relevant country) their legal guardian must give informed consent. Pediatric participants will be included in age-appropriate discussion in order to obtain assent.
• Participant must be ≥ 10 years of age at the time of signing the informed consent. Participant scheduled to receive clinical drug product supply must also weigh ≥ 40 kg. For participant scheduled to receive commercial drug product supply and weighing < 40kg, the Investigator must also consult with the Medical Monitor prior to inclusion.
• Participant has a diagnosis of synovial sarcoma or myxoid/round cell liposarcoma, confirmed by local histopathology and with evidence of translocation per below: – for synovial sarcoma, the presence of a translocation between SYT on the X chromosome and SSX1, SSX2 or, SSX4 on chromosome 18 (may be presented in the pathology report as t (X;18)) is required; – for myxoid/round cell liposarcoma, the presence of a translocation t (12;16)(q13;p11) or the variant translocation t (12;22)(q13;q12) is required.
• Participant has high-risk locally advanced (i.e. deeply seated, high grade, positive margins, large [≥5 cm], or locally recurrent) synovial sarcoma or myxoid/round cell liposarcoma.
• Participant with synovial sarcoma or myxoid/round cell liposarcoma who is:
  • Newly diagnosed, previously untreated; OR
  • Relapsed after surgery or radiotherapy for localized disease; OR
  • Relapsed 1 year after adjuvant/neoadjuvant therapy for localized disease.
• Male or female. Contraception requirements will apply at the time of leukapharesis and treatment.A representative tumor tissue specimen (archived or fresh biopsy) with associated pathology report should be available to perform NY-ESO-1 antigen expression analysis, unless a recent NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, has already been performed under a separate GSK-sponsored protocol or under another substudy. 

All the Inclusion Criteria in 1-7 must apply again prior to leukapheresis. In addition, the following criteria must also apply:

• Life expectancy ≥ 24 weeks.
• Participant has advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma. Unresectable refers to a tumor lesion in which clear surgical excision margins cannot be obtained without leading to significant functional compromise.
• Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a validated test in a designated central lab prior to leukapheresis.
  • NOTE: An HLA test result from the same designated central laboratory, following the same procedures, and performed under a separate GSK-sponsored protocol or under another substudy is acceptable.
• Participant’s tumor has been pathologically reviewed by a designated central laboratory with confirmed positive NY-ESO-1 expression defined as:
  • 30% of cells that are 2+ or 3+ by immunohistochemistry.
  • NOTE: A NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, and performed under a separate GSKsponsored protocol or under another substudy is acceptable.
• Left ventricular ejection fraction ≥ 45% with no evidence of clinically significant pericardial effusion.
• Performance status: for participants 60, or for participants < 16 and Lansky > 60, or for participants ≥ 16 and < 18 years of age, Karnofsky > 60, or for participants or for participants ≥ 18 years of age, Eastern Cooperative Oncology Group (ECOG) of 0-1.
• Participant must have adequate organ function and blood cell counts, within 7 days prior to the day of leukapheresis procedure (or first day of lymphodepletion during Treatment fitness assessment), as indicated by the following laboratory values.
• Hematological
• Absolute Neutrophil count (ANC) ≥1.5 x10^9 /L (without granulocute coloty-stimulating support);
• Absolute Lymphocyte count (ALC) ≥ 0.5 x 10^9 /L;
• Hemoglobin ≥ 8 g/dL or ≥ 5.6 mmol/L.
• Platelets ≥ 100 x10^9 /L (not achieved by transfusion).
• Creatinine clearance ≥ 40 mL/min.
• Participants who are ≥ 18 and < 65 years of age must be assessed either:
  • by 24-hour urine creatinine collection; OR
  • by using Serum Creatinine (Scr) via an estimated creatinine clearance calculated as below: Step 1: estimated glomerular filtration rate (GFR) to be obtained from the Chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009]:
  • Estimated GFR (mL/min/1.73m^2 ) = 141 × min(Scr/κ, 1), α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where:
  • Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min(Scr/κ,1) indicates the minimum of Scr/κ or 1, max(Scr/κ,1) indicates the maximum of Scr/κ or 1, and Age is in years.
  • Step 2: correction factor to be applied per the American National Kidney Foundation in order to obtain the estimated creatine clearance in mL/min Estimated CrCl (mL/min) = Estimated GFR (mL/min/1.73 m^2 ) × BSA (m2 ) / 1.73 m^2.
• Participants ≥ 65 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine EDTA GFR measurement, according to standard practice at the treating institution.  Participants <18 years of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear medicine EDTA GFR measurement or by serum creatinine collection, according to standard practice at the treating institution.
• Participants < 18 years of age must have GFR ≥ 70mL/min/1.73m^2 OR have a serum creatinine based on age/gender as follows:
  • Age Maximum serum creatinine (mg/dL) Male Female
  • Age 10 to < 13 years > 1.2
  • Age 13 to < 16 years > Male 1.5  | Female 1.4
  • Age 16 to < 18 years > Male 1.7 | Female 1.4
• Hepatic
• Total bilirubin
• Participants with Gilbert’s Syndrome (only if direct bilirubin ≤ 35%) | ≤ 1.5 x ULN (isolated bilirubin ≤ 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
• ALT ≤ 2.5 x ULN (or ≤ 5 x ULN if documented history of liver metastases)
• Coagulation
• 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 aPTT is within therapeutic range of intended use of anticoagulants Nutritional status.
• Albumin ≥ 3.5 g/dL
  • Participants may be transfused or receive growth factor treatment to meet minimum hematologic values up to 7 days prior to determining eligibility;
  • Adequate Organ Function will be reassessed for eligibility prior to lymphodepletion: if, upon consultation with the Medical Monitor, there is evidence from laboratory values that recovery from last anti-cancer treatment is underway, hematology labs may be considered acceptable and requirements waved to proceed with lymphodepletion.
• Participant is fit for leukapheresis and has adequate venous access for the cell collection.
• Male or female. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male Participants: Male participants are eligible to participate if they agree to the following during the intervention period starting at the first dose of chemotherapy for at least 12 months after receiving the T-cell infusion, or 4 months after there is no evidence of persistence/ gene modified cells in the participant’s blood, whichever is longer. Refrain from donating sperm Plus, either: Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR Must agree to use contraception/barrier as detailed below:
  • Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant (as a condom may break or leak);
  • Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.
• Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
  • Is not a WOCBP; OR
  • Is a WOCBP who will agree to use a barrier method (male condom) and use a contraceptive method that is highly effective (with a failure rate of < 1% per year) during the intervention period and for at least 12 months after receiving the T-cell infusion, or 4 months after there is no evidence of persistence/ gene modified cells in the participant’s blood, whichever is longer.  WOCBP should also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
  • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before any dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Female participants of childbearing potential (FCBP) must have a negative urine or serum pregnancy test.
• Safety assessments will be reassessed again prior to lymphodepletion. Treatment fitness will be established in consultation with Medical Monitor.

In addition, the following criteria must also apply:

• Participant has measurable disease according to RECIST v1.1.
• Supportive radiotherapy has not affected > 25% of bone marrow.
• A biopsy (excisional, incisional, or core) of non-target tumor tissue obtained within 90 days prior to initiating lymphodepleting chemotherapy is mandatory if cleanically feasible. This biopsy will be used as baseline for biomarker analyses. If it is not feasible to obtain a fresh biopsy, an archival tumor tissue (FFPE block) taken after completion of the participant’s last line of therapy, preferably within 90 days prior to initiating lymphodepleting chemotherapy, may be accepted at the discretion of the Medical Monitor (or designee). For participants who already provided a fresh biopsy for antigen expression and did not receive any supportive or intermediate anti-cancer therapy, the screening biopsy will be used for baseline.

• Participant has been previously treated for advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma.
• Central nervous system (CNS) metastases.
• Any other prior malignancy that is not in complete remission.
• Exceptions include:
  • completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (e.g., melanoma in situ, basal cell carcinoma, prostate cancer in-situ, periosteal osteosarcoma);
  • previous malignancies that have been definitively treated, and have been in remission for 5 years may be enrolled upon consultation with sponsor Medical Monitor or designee.
• Previous treatment with genetically engineered NY-ESO-1 specific T cells.
• Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody.
• Prior gene therapy using an integrating vector.
• Previous allogeneic hematopoietic stem cell transplant.
• Clinically significant systemic illness: a. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction, that in the judgment of the Investigator would compromise the participant’s ability to tolerate protocol therapy or significantly increase the risk of complications; OR
• Prior or active demyelinating disease. Please note in particular that mandatory washout period restrictions must be respected before starting leukapheresis.

In addition, participants are not eligible for leukapharesis if any of the following criteria apply: 

• Participant has history of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g., Crohn’s disease, systemic lupus) requiring steroids or other immunosuppressive treatments.
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection;
  • Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 or Class 4;
  • Uncontrolled clinically significant arrhythmia;
  • Acute coronary syndrome (angina or myocardial infarction) in last 6 months;
  • Interstitial lung disease (participants with existing pneumonitis as a result of radiation are not excluded; however, participants cannot be oxygen dependent).
• Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per Investigator assessment).
  • NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, persistent jaundice or cirrhosis.
• QTc > 480 msec.
  • NOTES: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read. The specific formula that will be used to determine eligibility for an individual participant should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual participant and then the lowest QTc value used to include or discontinue the participant from the trial. For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
• Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, other agents used in the study.
• Pregnant or breastfeeding females (due to risk to fetus or newborn).
• Any prior treatment-related toxicities must be CTCAE (Version 5.0) ≤ Grade 1 at the time of initiating study intervention (except for non-clinically significant toxicities e.g., alopecia, vitiligo). Participants with Grade 2 toxicities that are deemed stable or irreversible (e.g., chemotherapy related arthritis or tendinitis, skin discoloration or erythema) can be enrolled.
• Other standard of care lines of therapy are allowed only if guidelines and washout periods.
• Investigational treatment within 30 days or 5 half-lives (whichever is shorter) prior to leukapheresis. Investigational vaccines (other than NY-ESO-1 vaccines that are not allowed) must follow the washout period. Exceptions to this rule must be evaluated by the Investigator in agreement with the Sponsor’s Medical Monitor (or designee).
• Participant has active infection with HIV, HBV, HCV, EBV, CMV, syphilis, or HTLV as defined below:
  • Positive serology for HIV;
  • Active hepatitis B infection as demonstrated by test for hepatitis B surface antigen. Participants who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA and receive prophylaxis against viral reactivation;
  • Active hepatitis C infection as demonstrated by hepatitis C RNA test. Participants who are HCV antibody positive will be screened for HCV RNA by any RT PCR or bDNA assay. If HCV antibody is positive, eligibility will be determined based on a negative Screening RNA value;
  • Positive test for syphilis (spirochete bacterium);
  • Positive serology for HTLV 1 or 2.
• Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study. Treatment fitness will be established in consultation with Medical Monitor. Please note in particular that mandatory washout period restrictions must be respected before starting lymphodepletion.

In addition, participants cannot proceed with lymphodepletion or treatment if any of the following criteria apply:

• Participant has received cytotoxic therapy within 3 weeks prior to lymphodepleting chemotherapy.
• Systemic corticosteroids or any other immunosuppressive therapy within 2 weeks prior to lymphodepleting chemotherapy.
  • NOTE: Isolated doses of systemic corticosteroids are permitted to manage acute allergic reactions. Use of inhaled or topical steroids is not exclusionary.
• Participant has received radiotherapy to the target lesions within 3 months prior to lymphodepletion. A lesion with unequivocal progression may be considered a target lesion regardless of time from last radiotherapy dose.
  • NOTE: There is no washout period for palliative radiation to non-target lesions.
• Participant has received an anti-cancer vaccine within 2 months in the absence of tumor response. The participant should be excluded if their disease is responding to an experimental vaccine given within 6 months.
• Participant has received live vaccine within 4 weeks prior to lymphodepletion or intends to receive live vaccine during the 3 month period following administration of GSK3377794.
• Participant has received immune therapy (monoclonal antibody therapy, checkpoint inhibitors) within 4 weeks of lymphodepletion.
• Participant had major surgery ≤ 28 days of first dose of study intervention.

PRE-REGISTRATION

• Pathology from the resected brain metastasis must be consistent with a non-central nervous system primary site. Patients with or without active disease outside the nervous system are eligible (including patients with unknown primaries), as long as the pathology from the brain is consistent with a non-central nervous system primary site.
• Three or fewer (i.e., 0 to 3) unresected brain metastases (as defined on the post operative magnetic resonance imaging [MRI]) at the time of screening.
  • Note: Dural based metastases (e.g., commonly seen in breast cancer) are eligible.
• Unresected lesions must measure < 4.0 cm in maximal extent on the contrasted post-operative treatment MRI brain scan. The unresected lesions will be treated with SRS as outlined in the treatment section of the concept. 
  • Note: The metastases size restriction does not apply to the resected brain metastasis. 
• One brain metastasis must be completely (gross total resection) resected ≤ 30 days prior to pre-registration. 
  • NOTE: May not have had resection of more than one brain metastasis. 
• The resected brain metastasis must measure 2 cm or larger on the pre-operative MRI. 
• Resection cavity must measure < 5.0 cm in maximal extent and the resection must be complete (gross total resection) on the post-operative MRI obtained ≤ 30 days prior to pre-registration. 
• Karnofsky performance status of ≥ 60.
• For women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to pre-registration is required. 
• Men and women of childbearing potential must be willing to employ adequate contraception throughout the study and for men for up to 3 months after completing treatment. 
• A female of childbearing potential is a sexually mature female who:
  • has not undergone a hysterectomy or bilateral oophorectomy; or 
  • has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 
• Ability to complete an MRI of the head with contrast.
• The brain metastasis must be located > 5 mm of the optic chiasm and outside the brain stem.
• Must be fluent in English, Spanish, or French.

REGISTRATION

• Completion of all baseline electronic patient-reported outcome (ePRO) quality of life measures (or booklet quality of life measures) and Montreal Cognitive Assessment (MoCA).

• Must not have any prior whole brain radiation therapy.  Past radiosurgery to other lesions is allowed. 
  • NOTE: The surgically resected lesion cannot be the same location treated in the past with radiosurgery (i.e., repeat radiosurgery to the same location/lesion is not allowed on this protocol). 
• May not have primary germ cell tumor, small cell carcinoma, or lymphoma. 
• No evidence of leptomeningeal metastasis (LMD). 
  • NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion.

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

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

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.

• Clinical signs and symptoms consistent with the diagnosis of an acute ischemic stroke, and subject belongs to one of the following subgroups:
  • Subject has failed IV t-PA therapy;
  • Subject is contraindicated for IV t-PA administration;
  • IV-tPA given within 3 hours of symptom onset.
• Age ≥ 18 and ≤ 85.
• NIHSS score ≥ 8 and ≤ 25.
• Prestroke mRS score of ≤ 1.
• Intracranial arterial occlusion of the distal intracranial carotid artery or middle cerebral artery (M1/M2), anterior cerebral artery (ACA), posterior cerebral artery (PCA), basilar artery, or vertebral artery demonstrated with DSA.
• Thrombectomy procedure can be initiated within 8 hours from symptom onset (defined as time last known well [TLKW]) and at least one NeVa pass occurring within 8 hours.
• Imaging
  Inclusion Criteria:
  • Non-Contrast CT Selection (if CT Perfusion or MRI not utilized): ASPECTS 6-10 ; or
  • CT Perfusion core ≤ 50 cc; or
  • MRI DWI core ≤ 50 cc.
• Subject or legal representative is able and willing to give informed consent prior to the intervention

• Pre-existing medical neurological or psychiatric disease that would confound the neurological or functional evaluations; e.g., dementia with prescribed anti-cholinesterase inhibitor (e.g., Aricept).
• Cardiopulmonary resuscitation, cardiac arrhythmia resulting in hemodynamic instability (hypotension) that is not easily medically correctable, evidence of ongoing myocardial infarction, concern for pre-treatment pulmonary aspiration.
• Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
• Cerebral vasculitis.
• History of severe allergy to contrast medium.
• Known allergy to NeVa materials (nitinol, stainless steel).
• Suspicion of aortic dissection, septic embolus, or bacterial endocarditis.
• Systemic infection.
• Significant mass effect with midline shift.
• Evidence of intracranial tumor (except small meningioma [≤ 3 cm]).
• Any CT or MRI evidence of acute hemorrhage products on presentation.
• Inability to deploy NeVa device for at least one pass for any other reason.
• Life expectancy less than 6 months.
• Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed.
• Females you are pregnant or breastfeeding.
• Active malignancy.
• Stenosis or occlusion in a proximal vessel requiring treatment or preventing access to the thrombus.

• Male or female ≥ 16 and ≤ 75 years of age at Baseline.
  • Adolescent subjects at the age of 16 and 17 years old will be enrolled if approved by the country or regulatory/health authority. If these approvals have not been granted, only subjects ≥ 18 years old will be enrolled.
  • Adolescent subjects at the age of 16 and 17 years old must weigh ≥ 40 kg and meet the definition of Tanner Stage 5 at the screening visit.
• Diagnosis of ulcerative colitis for 90 days or greater prior to Baseline, confirmed by colonoscopy during the Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available.
• Active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and endoscopic sub score of 2 to 3 (confirmed by central reader).
• Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following treatments including, oral aminosalicylates, corticosteroids, immunosuppressants and/or biologic therapies, in the opinion of the investigator as defined below:
  • Note: An inadequate response, loss of response, or intolerance to Oral Aminosalicylates will NOT count towards eligibility for the following countries:
    • Austria, Czechia, Finland, Ireland, Italy, Latvia, Lithuania, Norway, Poland, Portugal, Spain, Sweden and United Kingdom.
  • Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide):
    • Signs and symptoms of persistently active disease, in the opinion of the investigator, during a current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide.
  • Corticosteroids:
    • Signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week, OR
    • Unable to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease, OR
    • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone, OR
    • Unable to taper oral budesonide to at or below 6 mg/day without recurrent active disease, OR
    • History of intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection).
  • Immunosuppressants:
    • Signs and symptoms of persistently active disease despite a history of at least one 90 day regimen of oral azathioprine (≥ 1.5 mg/kg/day; for subjects in Japan, China, and Taiwan only: ≥ 1.0 mg/kg/day), 6-MP (≥ 1 mg/kg/day; [for subjects in Japan, China, and Taiwan only: ≥ 0.6 mg/kg/day, rounded to the nearest available tablet of half tablet formulation] or a documented 6-TGN level of 230 –450 pmol/8 × 108 RBC or higher on the current dosing regimen), injectable MTX (≥ 15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for subjects in Japan and Taiwan only: documented trough level of 5 –10 ng/mL); OR
    • History of intolerance to at least one immunosuppressant (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, infection).
      • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study unless these subjects were previously treated with aminosalicylates, corticosteroids or immunosuppressants (azathioprine or 6-MP) and have inadequate response to, loss of response to or intolerance to the therapy as defined above.
  • Biologic Agents for UC:
    • Signs and symptoms of persistently active disease despite a history of any of the following:
      • at least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at 0, 2, and 6 weeks);
      • at least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous (SC) dose followed by one 80 mg SC dose [or one 80 mg SC dose, in countries where this dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart);
      • at least one 2-week induction regimen of golimumab (one 200 mg SC dose followed by one 100 mg SC dose at least 2 weeks apart);
      • at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2 and 6 weeks); OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify); OR
    • History of intolerance to at least one biologic agent (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection).
      • Note: Non-bio-IR subjects who have received a prior biologic for up to 1 year may be enrolled, however, subjects must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for inadequate response, loss of response or intolerance to aminosalicylates, corticorsteroids and/or immunosuppressants as defined above.
• Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit prior to study drug dosing.
  • Note: subjects with borderline serum pregnancy test at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of positive result.
  • For subjects in Ireland, a repeat serum pregnancy test ≥ 3 days later that is still borderline will result in screen failure.
  • If female, subject must meet the contraception criteria.
• Subject is judged to be in otherwise good health as determined by the Investigator based upon the results of medical history, laboratory profile, physical examination and a 12-lead electrocardiogram (ECG) performed during Screening.
• Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol. In Japan, if the subject is < 20 years old, a subject's parent or legal guardian must be willing to give written informed consent.

• Subject with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
• Current diagnosis of fulminant colitis and/or toxic megacolon.
• Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
• History of colectomy (total or subtotal) with ileoanal pouch, Kock pouch, or ileostomy for UC or is planning bowel surgery.
• Received treatment with rectal aminosalicylates or corticosteroids, other enemas/suppositories (other than required for endoscopy), within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
• Received cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 30 days prior to Baseline.
• Subjects who received azathioprine or 6-mercaptopurine within 10 days of Baseline.
• Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject on MTX or oral aminosalicylates who:
  • has not been on the current course of MTX for at least 42 days prior to Baseline, and has not been on stable doses for at least 28 days prior to Baseline;
  • has not been on stable doses of oral aminosalicylates for at least 14 days prior to Baseline;
  • has discontinued use of aminosalicylates within 14 days of Baseline.
• Subject on treatment with corticosteroids who meet the following:
  • Oral corticosteroid dose > 30 mg/day (prednisone or equivalent) or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral budesonide dose > 9 mg/day or has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral beclomethasone dose > 5 mg/day or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline.
  • Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject has active TB or meets TB exclusionary parameters.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject on UC-related antibiotics who has not been on stable doses for at least 14 days prior to Baseline or has discontinued these medications within 14 days of Baseline.
• Subjects who received any of the following biologic therapy:
  • infliximab, certolizumab, adalimumab, golimumab, vedolizumab, natalizumab, within 8 weeks prior to Baseline; OR
  • ustekinumab within 12 weeks prior to Baseline.
  • Note: If there is proper documentation of undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib, upadacitinib).
• Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except topical NSAIDs and the use of low dose aspirin for cardiovascular [CV] protection) within 7 days prior to Baseline.
• Subject received traditional Chinese medicine within 30 days prior to baseline.
• Subject received live vaccine(s) within 30 days (8 weeks for Japan) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (8 weeks for Japan) after the last dose of study drug.
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers during the Screening Period and through the end of the study.
• Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during study treatment.
• Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to Baseline, whichever is longer or is currently enrolled in an interventional study.
• Subject with positive C. difficile toxin stool assay during Screening.
• Infection(s) requiring treatment with intravenous anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit.
• Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study.
• Subject has current or past history of recurrent or disseminated (even a single episode) herpes zoster.
• Subject has current or past history of disseminated (even a single episode) herpes simplex.
• Subject has HBV, HCV, or human immunodeficiency virus (HIV) infection defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for subjects who are hepatitis B core antibody (HBc Ab) positive (+) subjects (and for Hepatitis B surface antibody positive (+) subjects where mandated by local requirements);
  • HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab);
  • HIV: confirmed positive anti-HIV antibody (HIV Ab).
• Prior or current gastrointestinal (GI) dysplasia, other than completely removed lowgrade dysplastic lesion in any biopsy performed during or before the Screening endoscopy.
• History of any malignancy, except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
• History of gastrointestinal (GI) perforation (other than appendicitis or penetrating injury), diverticulitis or significantly increased risk of GI perforation per investigator's judgment.
• Screening laboratory and other analyses show any of the following abnormal results:
  • Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) > 2 × upper limit of normal (ULN);
  • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
  • Total White Blood Cell (WBC) count < 2,500/μL;
  • Absolute neutrophil count (ANC) < 1,200/μL;
  • Platelet count < 100,000/μL;
  • Absolute lymphocytes count < 750/μL;
  • Hemoglobin < 9 g/dL.
• Female subject who is pregnant, breastfeeding or considering becoming pregnant during the study or within 30 days after the last dose of study drug, or has positive pregnancy test at Screening (serum) or Baseline (urine).
• History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
• History of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• For Japan subjects only: positive result of beta-D-glucan or two consecutive indeterminate results of beta-D-glucan (screening for Pneumocystis jiroveci infection).
• Received cytoapheresis treatment (GCAP, LCAP etc.) within 60 days prior to Baseline.
• For Japan subjects only: received ATM treatment (antibiotic combination therapy with amoxicillin, tetracycline and metronidazole) during the Screening Period.
• Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting or Moderate to severe congestive heart failure (New York Heart Association class III or IV).
• Conditions that could interfere with drug absorption including but not limited to short bowel syndrome (e.g., history of gastric bypass surgery).
• History of clinically significant medical condition or any other reason which, in the opinion of the investigator, would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug, or would put the subject at risk by participating in the protocol.

• Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
• Documented treatment failure from most recent prior therapy (e.g. tumor progression, clinical deterioration, or recurrence), and from at least one prior platinum-containing regimen in any treatment setting.
• Known tumor missense HRAS mutation.
• Measurable disease by RECIST v1.1.
• ECOG performance status of 0-1.
• Acceptable liver, renal and hematological function.

• Has disease that is suitable for local therapy administered with curative intent.
• Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g., mucosal melanoma).
• Known additional malignancy that is progressing or requires active treatment (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
• Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
• Prior treatment (at least 1 full treatment cycle) with a farnesyltransferase inhibitor (FTI).
• Any use of investigational therapy within 2 weeks of Cycle 1 Day 1 (C1D1) or 5 half-lives (whichever is longer).
• Received treatment for unstable angina within prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.
• Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1.
• Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
• Active, uncontrolled bacterial, viral or fungal infections requiring systemic therapy, including known history of infection with human immunodeficiency virus or an active infection with hepatitis B or hepatitis C.
• Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to its excipients.
• Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 or UDP-glucuronosyltransferase (UGT).
• Concomitant disease or condition that could interfere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subjects in this study.
• Female subjects who are pregnant or lactating

• Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology.
• HRAS wildtype determined by a test
• Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC.

• Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g., mucosal melanoma).
• Concomitant disease or condition that could interefere with the conduct of the study or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.

• Pathologically proven diagnosis of extensive stage small cell lung cancer.
• Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography [PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging [MRI] optional per treating physician); atezolizumab should continue through randomization. Patients must be randomized within 9 weeks of last dose of etoposide/platinum or 6 weeks from completion of prophylactic cranial irradiation (PCI).
• At the time of enrollment, patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST]) and 3 or fewer observable liver metastases and no evidence of progressive disease (per RECIST) at time of enrollment.
• Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 14 days prior to registration;
  • Imaging within 42 days prior to registration to include:
    • MRI brain with contrast or CT brain with contrast;
    • CT chest, abdomen and pelvis or whole body PET/CT scan after the fourth cycle of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration.
• Absolute neutrophil count (ANC) ≥ 1,000/cells/mm^3 (within 14 days prior to registration).
• Platelets ≥ 75,000 cells/mm^3 (within 14 days prior to registration).
• Hemoglobin ≥ 8 g/dL (within 14 days prior to registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 x ULN (AST and/or ALT ≤ 5 ULN for patients with liver involvement) (within 14 days prior to registration).
• Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 ULN for patients with documented liver involvement or bone metastases) (within 14 days prior to registration).
• Adequate renal function ≤ 2.0 x ULN.
• Adequate renal function within 30 days prior to registration defined as follows: glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m^2.
• Upfront central nervous system (CNS) radiotherapy for treatment of brain metastases is permitted provided there is no evidence of CNS progression at the time of randomization and patients are clinically stable on a dose of steroids < 10 mg prednisone a day or equivalent. Upfront radiation therapy of symptomatic metastatic site is permissible if causing patient pain or impending fracture.
• Patients with bone metastases are eligible. However, to assess response after radiation for bone metastases, must order at least diagnostic CT scan to measure response.
• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration.
  • Note: Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
    • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastatic sites detectable after induction systemic therapy. Each visible bone metastasis on radiographic scan count as one site. For site of bony metastases, must order diagnostic CT scan for assessment of response.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 5 years prior to randomization. Cancers with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome are eligible (such as adequately treated carcinoma in situ of the cervix or oral cavity; localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent).
• Prior radiotherapy except in the thorax, where there may be some overlap in the mediastinum and spine, as long as overlap fields meet dose constraints.
• History of autoimmune disease, including, but not limited to: systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g., Crohn's, ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome; Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple sclerosis; vasculitis; or glomerulonephritis.
  • Note: the following are eligible:
    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible;
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible;
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Patients with psoriasis must not have ocular manifestations within the past year;
  • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled on topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%).
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or oral steroids).
• Severe, active co-morbidity defined as follows:
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
• Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL).
• Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests.
• Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months.
• History of recent myocardial infarction within 6 months prior to registration.
• Clinically significant interstitial lung disease.
• Pregnancy:
  • Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 5 months (150 days) after the last dose of study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately;
  • Women who are breastfeeding and unwilling to discontinue.
• History of allogeneic organ transplant.
• Patients who have had immunotherapy-induced pneumonitis.

• Pathologically proven diagnosis of extensive stage small cell lung cancer.
• Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography [PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging [MRI] optional per treating physician); atezolizumab should continue through randomization. Patients must be randomized within 9 weeks of last dose of etoposide/platinum or 6 weeks from completion of prophylactic cranial irradiation (PCI).
• At the time of enrollment, patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST]) and 3 or fewer observable liver metastases and no evidence of progressive disease (per RECIST) at time of enrollment.
• Patients presenting with a pleural effusion will be eligible if thoracentesis is cytologically negative and non-bloody or if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging.
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 14 days prior to registration;
  • Imaging within 42 days prior to registration to include:
    • MRI brain with contrast or CT brain with contrast;
    • CT chest, abdomen and pelvis or whole body PET/CT scan after the fourth cycle of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration.
• Absolute neutrophil count (ANC) ≥ 1,000/cells/mm^3 (within 14 days prior to registration).
• Platelets ≥ 75,000 cells/mm^3 (within 14 days prior to registration).
• Hemoglobin ≥ 8 g/dL (within 14 days prior to registration).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 14 days prior to registration).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 x ULN (AST and/or ALT ≤ 5 ULN for patients with liver involvement) (within 14 days prior to registration).
• Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 ULN for patients with documented liver involvement or bone metastases) (within 14 days prior to registration).
• Adequate renal function ≤ 2.0 x ULN.
• Adequate renal function within 30 days prior to registration defined as follows: glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m^2.
• Upfront central nervous system (CNS) radiotherapy for treatment of brain metastases is permitted provided there is no evidence of CNS progression at the time of randomization and patients are clinically stable on a dose of steroids < 10 mg prednisone a day or equivalent. Upfront radiation therapy of symptomatic metastatic site is permissible if causing patient pain or impending fracture.
• Patients with bone metastases are eligible. However, to assess response after radiation for bone metastases, must order at least diagnostic CT scan to measure response.
• For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration.
  • Note: Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
    • Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

• Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastatic sites detectable after induction systemic therapy. Each visible bone metastasis on radiographic scan count as one site. For site of bony metastases, must order diagnostic CT scan for assessment of response.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 5 years prior to randomization. Cancers with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome are eligible (such as adequately treated carcinoma in situ of the cervix or oral cavity; localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent).
• Prior radiotherapy except in the thorax, where there may be some overlap in the mediastinum and spine, as long as overlap fields meet dose constraints.
• History of autoimmune disease, including, but not limited to: systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g., Crohn's, ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome; Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple sclerosis; vasculitis; or glomerulonephritis.
  • Note: the following are eligible:
    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible;
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible;
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
  • Patients with psoriasis must not have ocular manifestations within the past year;
  • Rash must cover less than 10% of body surface area (BSA);
  • Disease is well controlled on topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%).
• No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or oral steroids).
• Severe, active co-morbidity defined as follows:
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications;
  • Active tuberculosis;
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). (The HCV RNA test must be performed for patients who have a positive HCV antibody test).
• Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL).
• Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART);
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
  • A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based tests.
• Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid therapy of > 10 mg prednisone daily or equivalent at the time of registration. Inhaled corticosteroids are not exclusionary.
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 3 months.
• History of recent myocardial infarction within 6 months prior to registration.
• Clinically significant interstitial lung disease.
• Pregnancy:
  • Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 5 months (150 days) after the last dose of study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately;
  • Women who are breastfeeding and unwilling to discontinue.
• History of allogeneic organ transplant.
• Patients who have had immunotherapy-induced pneumonitis.

• Male or female between 6 months through 36 months of age at the time of informed consent as clinical diagnosis of IS, confirmed by video-electroencephalogram (EEG) analysis, and hypsarrhythmia on EEG at screening according to the Burden of Amplitudes and Epileptiform Discharges (BASED) scale score.
• As assessed by the investigator has no or partial response to at least 2 out of the 3 therapies of adrenocorticotrophic hormone (ACTH), vigabatrin, and glucocorticoids (i.e. prednisolone), or has no or partial response to at least 1 out of the 3 therapies of ACTH, vigabatrin, and glucocorticoids and is contraindicated to and/or refused by the patient’s legal representative(s) for treatment with one or both other 2 therapies.
• Patient has general good health (defined as the absence of any clinically relevant abnormalities as determined by the investigator) based on physical and neurological examinations, medical history, normal renal function and electrocardiogram (ECG), and clinical laboratory values completed during the Screening Period visit (Visit 1).

• Patient considered by the investigator, for any reason (including, but not limited to, the risks described as precautions and warnings in the current version of the investigator’s brochure for investigational product) to be an unsuitable candidate to receive the investigational product.
• Patient has known or suspected allergy to the investigational product or apple juice.
• Patient has clinically significant renal impairment, defined as creatinine > mg/dL or blood urea nitrogen > 2 × upper limit of normal (ULN); clinically significant liver dysfunction, defined as total bilirubin ≥ 2 × ULN, or aspartate aminotransferase or alanine aminotransferase ≥ 3 × ULN; has clinically significant abnormal laboratory values; the investigator may deem the patient eligible if he/she judges the laboratory values to be not clinically significant.
• Patient has an ongoing or known history of human immunodeficiency virus infection, or chronic hepatitis B or C.
• Patient has a clinically significant abnormality on ECG that, in the opinion of the investigator, increases the safety risks of participating in the study.
• Patient has a neurodegenerative disorder as the underlying cause of IS.
• Patient has a known history of aspiration pneumonia within the past year.
• Patient has previously participated in another clinical study of the investigational product or received any investigational drug or device or investigational therapy within 30 days of study entry.
• Patient has received therapy with felbamate, cannabinoids, ketogenic diet or vagus nerve stimulation within 14 days of screening.
• Patient has received therapy with a medication known to be a CYP3A4 substrate and whose PK has been shown to be impacted in the presence of a CYP3A4 inhibitor within 14 days impacted in the presence of a CYP3A4 inhibitor within 14 days of screening.
• Patient has not remained at stables doses of all drugs used for treating epileptic seizures for at least 14 days prior to screening (except for rescue medications used for acute treatment of breakthrough seizures which are not known to be CYP3A4 substrates and whose PK has not been shown to be impacted in the presence of a CYP3A4 inhibitorist of CYP3A4 substrates]).
• Patient has a lethal or potentially lethal condition other than infantile spasms, with a significant risk of death before 18 months of age such as non-ketotic hyperglycinemia.
• Patient has an underlying metabolic disease associated with glucose intolerance (e.g., glucose transporter deficiencies).
• Patient has a body weight below 5 kg.

• Patients over the age of 18 years old.

• Children.

• Subject is ≥ 18 years and ≤ 75 years of age and has voluntarily agreed to participate by giving written informed consent in accordance with ICH GCP Guidelines and applicable local regulations.
• Histologically confirmed HCC, not amenable to transplant or resection. Subjects may undergo loco-regional therapy after enrolment but should not be amenable to further loco-regional therapy at the time of lymphodepletion; OR g-histologically confirmed diagnosis of another AFP expressing tumor (e.g., cholangiocarcinoma).
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria prior to lymphodepletion.
• Progressive disease following or intolerant of or refuses standard of care systemic therapy prior to lymphodepletion.
• Positive for HLA-A*02:01 (or any A*02:01 P group allele). The Sponsor will review the results of HLA typing for inclusion alleles, and will adjudicate subject eligibility based on HLA results.
• Group 1, 2, 3, (HCC) Subjects must have biopsy tissue available for AFP expression evaluation prior to enrollment unless considered unsafe. Either an archival specimen (taken within the past 12 months from Screening) or a new biopsy will be required for AFP expression in tumor tissue. Non-cancerous biopsy is also required prior to enrolment. Subjects will be eligible for enrollment if they meet either one of these AFP expression criteria:
  • AFP expression of ≥ 1+ in ≥ 20% of tumor cells by immunohistochemistry and their non-cancerous liver tissue has ≤ 5% cells stained for AFP at any intensity by immunohistochemistry;
  • Serum AFP levels of ≥100ng/mL and their non-cancerous liver tissue has ≤ 5% cells stained for AFP at any intensity by immunohistochemistry. Subjects with serum AFP levels within the normal range at the time of screening are unlikely to have AFP expressing tumors and generally should not undergo new tumor biopsy for the purpose of participating in this study.
  • Group 4 (other AFP expressing tumor types) Subjects must have biopsy tissue available for AFP expression evaluation prior to enrollment unless considered unsafe. Either an archival specimen (taken within the past 12 months from Screening) or a new biopsy will be required for AFP expression in tumor tissue. Non-cancerous biopsy is also required prior to enrolment, for subjects with underlying liver disease. Subjects will be eligible for enrollment if they meet the following AFP expression criterion:
    • Serum AFP levels of ≥ 100ng/mL and their non-cancerous liver tissue (if applicable) has ≤ 5% cells stained for AFP at any intensity by immunohistochemistry. Subjects with serum AFP levels within the normal range at the time of screening are unlikely to have AFP expressing tumors and generally should not undergo new tumor biopsy for the purpose of participating in this study.
• Life expectancy of > 4 months.
• Child-Pugh score ≤ 6.
• Eastern Cooperative Oncology Group (ECOG) 0-1.
• Female subjects of childbearing potential (FCBP) must have a negative serum pregnancy test.
• NOTE: FCBP is defined as premenopausal and not surgically sterilized. FCBP must agree to use effective birth control or to abstain from heterosexual activity throughout the study, starting at the first dose of chemotherapy for at least 12 months thereafter or 4 months after there is no evidence of persistence or gene modified cells are in the subject’s blood, whichever is longer. FCBP must also agree to refrain from egg donation, storage, or banking during these same time periods. Effective contraceptive methods include intra-uterine device, oral and injectable hormonal contraception, or 2 adequate barrier methods (e.g., diaphragm with spermicide, cervical cap with spermicide, or female condom with spermicide). Spermicides alone are not an adequate method of contraception; OR male subjects must be surgically sterile or agree to use a double barrier contraception method or abstain from heterosexual activity with a female of childbearing potential starting at the first dose of chemotherapy and for at least 6 months thereafter. Male subjects must also agree to refrain from sperm donation, storage, or banking during these same time periods.
  Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable by local Regulatory Agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.

• Positive for any HLA-A*02 allele other than HLA-A*02:01 P Group, HLA-A*02:03 P group or null alleles, or positive for the following alleles: HLA-C*04:04 or HLA-B*51:03. The Sponsor will review the results of HLA typing for exclusion alleles, and will adjudicate subject eligibility based on HLA results.
• Prior liver transplant.
• Received the following prior to leukapheresis:
  • Cytotoxic chemotherapy, immune therapy and biological therapy within 3 weeks;
  • Corticosteroids or any other immunosuppressive therapy within 2 weeks.
  • NOTE: Use of inhaled or topical steroids is not exclusionary.
  • Sorafenib/Regorafenib/Lenvatinib within 1 week;
  • Cabozantinib within 2 weeks;
  • Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune Study Physician.
• Received the following prior to lymphodepleting chemotherapy:
  • Cytotoxic chemotherapy or loco-regional therapy within 3 weeks, liver directed radiation therapy within three months;
  • Corticosteroids or any other immunosuppressive therapy within 2 weeks.
  • NOTE: Use of inhaled or topical steroids is not exclusionary.
  • Bone/soft tissue directed palliative radiotherapy within 4 weeks;
  • Investigational treatment or clinical trial within 4 weeks;
  • Sorafenib/Regorafenib/Lenvatinib within 1 week;
  • Cabozantinib within 2 weeks;
  • Prior cancer-directed immunotherapy within 4 weeks, including monoclonal antibodies against PD-1 receptor or ligand;
  • Use of an experimental vaccine within 2 months in the absence of tumor response. The subject should be excluded if their disease is responding to an experimental vaccine given within 6 months;
  • Any previous gene therapy using an integrated vector;
  • Duration of treatment free intervals for any other anti-cancer therapies must be discussed with Adaptimmune Study Physician.
• Toxicity persisting from previous anti-cancer therapy of ≥ Grade 2 (except for non-clinically significant toxicities; e.g., alopecia, vitiligo). Subjects with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) can be enrolled on a case-by-case basis with prior consultation and agreement with the Sponsor Study Physician.
• Major surgery within 4 weeks prior to lymphodepletion; subjects should have been fully recovered from any surgical related toxicities.
• Bleeding ≥ Grade 2 in the past 3 months prior to lymphodepletion.
• Therapeutic anticoagulation from lymphodepletion until platelet count recovery (prophylactic heparin allowed).
• Clinically or radiographically detectable ascites (beyond trace/rim of ascites) or ascites requiring medication.
• Clinically detectable hepatic encephalopathy or hepatic encephalopathy requiring medication.
• Active viral hepatitis.  
• Subjects positive for hepatitis B surface antigen not on antiviral treatment/prophylaxis or subjects with detectable hepatitis B DNA:
  • Subjects with resolved (surface antigen negative, core antibody positive) or chronic stable (surface antigen positive) hepatitis B on antiviral treatment/prophylaxis with DNA levels of ≤ 100 IU/mL are allowed with HBV DNA monitoring after treatment;
  • Subjects with hepatitis C allowed provided they meet all other eligibility criteria.
• Positive serology for HIV.
• Positive serology for HTLV 1 or 2.
• History of chronic or recurrent (within the last year) severe autoimmune or immune mediated disease requiring steroids or other immunosuppressive treatments. Subjects with history of idiopathic autoimmune hepatitis are excluded. Subjects who experienced hepatitis during treatment with check point inhibiting antibodies are not excluded.
• Subject has brain metastases.
• Other active malignancy besides HCC or other eligible AFP expressing tumor types within 3 years:
  • Subjects must be in complete remission from prior malignancy in order to be eligible to enter the study;
  • Adequately treated malignancies not likely to require therapy (e.g., completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma) are eligible to enter the study.
• Electrocardiogram (ECG) showing clinically significant abnormality at Screening or showing a QTc interval ≥ 450 msec in males and ≥ 470 msec in females (≥ 480 msec for subjects with Bundle Branch Block (BBB) over consecutive ECGs).
• Bacterial or opportunistic infection within 3 months of treatment (upper respiratory infection and uncomplicated urinary tract infection allowed).
• Uncontrolled intercurrent illness considered by the Investigator to add appreciable risk to study participation, including but not limited to:
  • Clinically significant cardiac disease defined by CHF New York Heart Association (NYHA) > Class 1; uncontrolled clinically significant arrhythmia in last 6 months; Acute Coronary Syndrome (ACS) (angina or myocardial infarction) in last 6 months;
  • Oxygen dependent lung disease;
  • Clinically significant psychiatric illness/social situations that would limit compliance with study requirements;
  • History of stroke or central nervous system bleeding; transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in last 6 months.
• Pregnant or breastfeeding.
• Alcohol or illicit drug dependency.
• Known contraindication to cyclophosphamide, fludarabine, mesna, G-CSF or other agents associated with study treatment.

Eligibility last updated 12/30/21. Questions regarding updates should be directed to the study team contact.

• Participants diagnosed with Atopic Dermatitis (AD) as defined by the Hanifin and Rajka criteria.
• Participants with AD duration of at least 3 months (participant/parent/guardian may verbally report signs and symptoms of AD with onset at least 3 months prior).
• Participants with IGA score of 2 to 3 at the screening and baseline visits.
• Participants with % BSA (excluding scalp) of AD involvement of 3% to 20% at screening and baseline visits.
• For children aged 6 years to < 12 years, baseline itch NRS score ≥ 4.
• Participants/guardians who agree to discontinue all agents used by the participant to treat AD from the screening visit through the final safety follow-up visit.
• Participants with at least 1 target lesion that measures at least 5 cm^2 at the screening and baseline visits. The target lesion must be representative of the participant's disease state but not located on the hands, feet, or genitalia.
• Willingness to avoid pregnancy or fathering a child for the duration of study participation.

• An unstable course of AD (spontaneously improving or rapidly deteriorating) as determined by the investigator over the previous 4 weeks before the baseline visit. -Concurrent conditions and history of other diseases as follows:
  • Immunocompromised;
  • Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit;
  • Active acute bacterial, fungal, or viral skin infection within 1 week before the baseline visit;
  • Any other concomitant skin disorder, pigmentation, or extensive scarring that in the opinion of the investigator may interfere with the evaluation of AD lesions or compromise participant safety;
  • Presence of AD lesions only on the hands or feet without prior history of involvement of other classic areas of involvement such as the face or the flexural folds;
  • Other types of eczema;
  • Chronic asthma requiring more than 880 µg of inhaled budesonide or equivalent high dose of other inhaled corticosteroids.
• Any serious illness or medical, physical, or psychiatric condition(s) that, in the investigator's opinion, would interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
• Use of any of the following treatments within the indicated washout period before the baseline visit:
  • 5 half-lives or 12 weeks, whichever is longer – biologic agents (e.g., dupilumab);
  • 4 weeks – systemic corticosteroids or adrenocorticotropic hormone analogues, cyclosporin, methotrexate, azathioprine, or other systemic immuno-suppressive or immunomodulating agents (e.g., mycophenolate or tacrolimus);
  • 2 weeks – immunizations with live-attenuated vaccines; sedating antihistamines unless on a long-term stable regimen (nonsedating antihistamines are permitted).
  • Note: Live-attenuated vaccines are not recommended during the VC period. Note: COVID-19 vaccination is allowed;
  • 1 week – use of topical treatments for AD (other than bland emollients; e.g., Aveeno® creams, ointments, sprays, soap substitutes), such as topical antipruritics (e.g., doxepin cream), corticosteroids, calcineurin inhibitors, PDE4 inhibitors, coal tar (shampoo), topical antibiotics, or antibacterial cleansing body wash/soap.
  • Note: Diluted sodium hypochlorite "bleach" baths are allowed as long as they do not exceed 2 baths per week and their frequency remains the same throughout the study.
• Participants who have previously received JAK inhibitors, systemic or topical.
• Ultraviolet light therapy or prolonged exposure to natural or artificial sources of UV radiation (e.g., sunlight or tanning booth) within 2 weeks prior to the baseline visit and/or intention to have such exposure during the study, which is thought by the investigator to potentially impact the participant's AD.
• Positive serology test results at screening for HIV antibody.
• Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) before the baseline visit with another investigational medication or current enrollment in another investigational drug protocol.
• In the opinion of the investigator, unable or unlikely to comply with the administration schedule and study evaluations.
• Employees of the sponsor or investigator or otherwise dependents of them.

Eligibility last updated 5/9/22. Questions regarding updates should be directed to the study team contact.

NON- BAVM recruit (living)

• Definite clinical HHT diagnosis (at least 3 Curacao criteria):
  • Spontaneous recurrent nosebleeds;
  • Mucocutaneous telangiectasia at characteristic sites (lips, oral cavity, fingers or nose);
  • Organ AVM (lung, brain, liver, renal, spinal or limb AVMs or GI telangiectasia);
  • An affected first-degree relative by same criteria.
• Genetic diagnosis of HHT.

BAVM recruit (living) or BAVM recruit (deceased)

• Presence of BAVM.
• Definite clinical HHT diagnosis (at least 3 Curacao criteria):
  • Spontaneous recurrent nosebleeds;
  • Mucocutaneous telangiectasia at characteristic sites (lips, oral cavity, fingers or nose);
  • Organ AVM (lung, brain, liver, renal, spinal or limb AVMs or GI telangiectasia);
  • An affected first-degree relative by same criteria.
• Genetic diagnosis of HHT.
• Able to provide informed consent in person or via a parent or legal authorize representative.

• None.

• Adult female subjects aged 18 to 75 years, inclusive, or adult male subjects aged 50 to 75 years, inclusive, at the time of signing the ICF prior to initiation of any study-specific activities/procedures.
• A current diagnosis of symptomatic PAH classified by one of the following:
  • Idiopathic PAH (IPAH) or heritable pulmonary arterial hypertension (HPAH);
  • PAH associated with connective tissue diseases (CTD-APAHs):
    • Systemic sclerosis;
    • Mixed CTD or overlap syndrome;
    • Systemic lupus erythematosus.
  • Other CTD established by ACR/EULAR guidelines;
  • PAH associated with anorexigen or methamphetamine use;
  • Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after surgical repair.
• 6MWD ≥ 150 meters and ≤ 550 meters at screening.
• WHO FC II or III symptomatology.
• Treatment with standard of care PAH background therapies.
• Documentation of cardiac catheterization within the screening period that is consistent with the diagnosis of PAH and meeting all the following criteria, to be confirmed by a central hemodynamic core laboratory:
  • Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg (at rest);
  • Pulmonary capillary wedge pressure ≤ 15 mmHg, or mean left atrial pressure (mLAP) or left ventricular-end diastolic pressure (LVEDP) ≤ 15 mmHg in the absence of left atrial obstruction;
  • PVR ≥ 400 dyne•s/cm^5.
• Pulmonary function tests (PFTs) at screening with the following criteria met:
  • Forced expiratory volume in 1 second (FEV1) divided by the forced vital capacity (FVC) ≥ 760% (predicted);
  • Total lung capacity (TLC) or FVC ≥ 70% predicted.

• Evidence of chronic thromboembolic disease or acute pulmonary embolism as assessed by ventilation-perfusion (V/Q) scan, computed tomography (CT)-angiogram, or pulmonary angiogram prior to screening.
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during screening visit after a period of rest.
• Systolic blood pressure < 90 mm Hg during screening and baseline visits.
• WHO Pulmonary Hypertension Group 2-5.
• Human immunodeficiency virus (HIV)-associated PAH.
• History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
  • Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis (AS), mild mitral stenosis (MS), moderate mitral regurgitation (MR);
  • Mechanical cardiac valve requiring anticoagulation;
  • Pericardial constriction or pericardial effusion with tamponade physiology;
  • Restrictive cardiomyopathy;
  • Left ventricular ejection fraction (LVEF) ≤ 50% by echocardiography (ECHO) within 6 weeks prior to screening; if  ECHO from the prior 6 weeks is not available, the screening ECHO results may be used to establish this criterion.
  • Note: If ECHO images are not adequate to provide an accurate estimate of LVEF then a multigated acquisition (MUGA) or cardiac magnetic resonance imaging (cMRI) scan or single photon emission computed tomography (SPECT) imaging can be used to obtain an accurate LVEF.
  • Left Atrial Area greater than 29cm2 by ECHO within 6 weeks prior to screening; if historical ECHO from the prior 6 weeks is not available, screening ECHO results may be used to establish this criterion. g. Documented uncontrolled symptomatic coronary disease (ie, unstable angina or percutaneous coronary intervention or coronary artery bypass graft within 12 months prior to screening, or planned coronary intervention or coronary artery bypass surgery).
• Untreated obstructive sleep apnea.
• History of atrial septostomy within 180 days prior to screening.
• Pulmonary venous occlusive disease (PVOD).
• Subjects with a history of portopulmonary hypertension or portal hypertension due to cirrhosis classified as Child-Pugh Class A or higher; or baseline ALT or AST > 2 x ULN or Total Bilirubin ≥ 2 X ULN.
• History of malignancy within 5 years prior to screening, with the exception of localized nonmetastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix.
• History of a potentially life-threatening cardiac arrhythmia with an ongoing risk.
• Uncontrolled bacterial, viral, or fungal infections which require systemic therapy.
• Severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP administration (eg, history of intracranial hemorrhage), or absolute neutrophil count (ANC) < 1 x 10^9 /L or platelet count < 50 x10^ 9 /L.
• Any musculoskeletal disease or any other disease that limits evaluation of 6MWT.
• Pregnant or nursing or intends to become pregnant during the duration of the study.
• Body weight < 40 kg at screening.
• Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 via CKD-epi (Levey, 2009) at screening or requires dialytic therapy or hemofiltration.
• Hemoglobin (Hgb) concentration < 8.5 g/dL at screening.
• Evidence of active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infections.
• Inhaled prostanoids; these drugs may be withdrawn ≥ 4 weeks prior to screening, if clinically indicated.
• Use of oral anticoagulants (i.e., coumadin warfarin or novel oral anticoagulants [NOAC]) at randomization; if on coumadin warfarin or a NOAC, these drugs can be withdrawn, if clinically appropriate, during the screening period, and subjects should have normal coagulation parameters prior to the randomization for examples of prohibited anticoagulants).
• Requirement of intravenous (IV) inotropes (i.e., levosimendan, dopamine, dobutamine, milrinone, norepinephrine) other than an IV prostanoid within 4 weeks of screening. Prior/Concurrent Clinical Study Experience.
• Prior participation in GB002 studies and/or prior treatment with GB002.
• Currently participating in or has participated in a study of an investigational agent or has used an investigational device for the treatment of PAH within 4 weeks prior to screening.
  • Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks or at least 5 half-lives (whichever is greater) after the last dose of the previous investigational agent.
• Current use of inhaled tobacco and/or inhaled marijuana.
• Current alcohol use disorder as defined by DSM-5 and/or a positive test for drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine [PCP]). Retest may be performed for potential false positive results. Subjects with a history of methamphetamine abuse must be abstinent for a minimum of 1 year prior to screening, in the opinion of the investigator.as documented by at least two negative urine or serology tests during the 12 months prior to screening. Certain drugs may be allowed IF prescribed by medical personnel and is under medical supervision for documented medical conditions (ie, opioids for pain, benzodiazepines for anxiety). Ingestible or topical marijuana is allowed, per local restrictions and regulations.
• Subjects with a history of severe milk protein allergy. In addition, subjects with known intolerance or hypersensitivity to lactose who, in the opinion of the investigator, may experience severe symptoms following the ingestion of lactose. 
• QTcF of > 480 msec recorded on a screening or baseline ECG or receiving concurrent treatment with medications that prolong QT interval. 
• Have any other condition or reason that, in the opinion of the Investigator or Medical Monitor, would prohibit the subject from participating in the study.

Eligibility last updated 1/25/22. Questions regarding updates should be directed to the study team contact.

• Diagnosis of Partial Lipodystrophy.

• Previous treatment with metreleptin.

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

• Age > 18 years old.
• ECOG performance status (PS) 0, 1 or 2.
• Clinical and radiographic evidence suggesting a diagnosis of a diffuse glioma, or a prior diagnosis of a diffuse glioma.
• Diffuse gliomas include diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma and anaplastic oligodendroglioma.
• Planned neurosurgical procedure for purposes of biopsy or resection of suspected or previously diagnosed brain tumor as part of routine clinical care.
• Willing to undergo neurosurgical resection or biopsy at Mayo Clinic (Rochester, MN).
• Ability to understand and the willingness to sign a written informed consent document.

• Vulnerable populations:
  • Pregnant women;
  • Prisoners;
  • Mentally handicapped.
• Patients who are not appropriate candidates for surgery due to current or past medical history or uncontrolled concurrent illness.

• Age ≥ 18 years.
• Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of WHO pulmonary arterial hypertension (PAH) Group .1 in any of the following subtypes:
  • Idiopathic PAH;
  • Heritable PAH;
  • Drug/toxin-induced PAH;
  • PAH associated with connective tissue disease;
  • PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following repair.
• Symptomatic PAH classified as WHO Functional Class II or III.
• Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of 2: 5 Wood units (WU).
• On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice. 
• 6MWD 2: 150 and :S 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value).
• Females of childbearing potential must:
  • Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; she must agree to ongoing urine or serum pregnancy testing during the study and until 8 weeks after the last dose of the study drug;
  • If sexually active, have used, and agree to use, highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment;
  • Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study treatment.
• Male participants must:
  • Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy;
  • Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study treatment.
• Ability to adhere to study visit schedule and understand and comply with all protocol requirements.
• Ability to understand and provide written informed consent.

• Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5.
• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH Group I should also include schistosomiasis APAH and pulmonary veno-occlusive disease.
• Hemoglobin (Hgb) at screening above gender-specific upper limit of normal (ULN), per local laboratory test.
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure> 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest.
• Baseline systolic BP < 90 mmHg at screening.
• Pregnant or breastfeeding women.
• Any of the following clinical laboratory values at the screening visit:
  • Estimated glomerular filtration rate (eGFR) < 30 mL/min/m^2 (as defined by MDRD equation);
  • Serum alanine aminotransferase or aspartate aminotransferase levels > 3 x ULN or total bilirubin > 1.5 x ULN.
• Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent.
• Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) and/or excipients or known allergic reaction to either one.
• Have full or partial pneumonectomy.
• Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing no more than mild interstitial lung disease (ILD) perfonned at the screening visit or 1 year to it.
• Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible).
• History of more than mild obstructive sleep apnea that is untreated.
• Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C).
• History of restrictive, constrictive or congestive cardiomyopathy.
• History of atrial septostomy within 180 days prior to the screening visit.
• Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during the screening period.
• Personal or family history oflong QT syndrome (LQTS) or sudden cardiac death.
• Left ventricular ejection fraction < 45% on historical echocardiogram within 6 months prior to the screening visit or pulmonary capillary wedge pressure > 15 mmHg as determined in the Screening Period RHC.
• Any symptomatic coronary disease events within 6 months (prior myocardial infarction, percutaneous coronary interventi on, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months of the screening visit.
  • Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions.
• Cerebrovascular accident within 3 months prior to the screening visit.
• Acutely decompensated heart failure within 30 days prior to the screening visit, as per investigator assessment.
• Significant (2: 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, mitral stenosis and more than mild aortic valve stenosis.
• Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to the screening visit.

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

Eligibility last updated 9/8/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• Age ≥ 18 years
• HIV-1 infected with the potential to have been cured of infection in the course of routine clinical care in the opinion of the treating physician and study team
• Have an undetectable plasma HIV-1 RNA and undetectable proviral DNA on suppressive antiretroviral therapy on at least two consecutive measures for at least 6 months
• Able and willing to either abstain from sexual activity or use barrier contraceptives during the ATI
• Negative serum β-HCG pregnancy test in women with childbearing potential
• Have the ability to give appropriate informed consent.

Exclusion Criteria

• Women who are pregnant or nursing
• Women who can become pregnant who are unable or unwilling to use both barrier and pharmacologic contraceptives during the ATI
• Previous or current infections that are at high risk of reactivating with immune suppression, in whom there are no effective antimicrobial prophylaxis options
• Advanced cardiopulmonary or liver disease
• History of untreated solid or hematologic malignancies
• Evidence of active viral replication in patients co-infected with Hepatitis B virus (HBV). Treatment should be provided to suppress HBV replication with agents that do not have activity against HIV (ie entecavir) prior to consideration for ATI.
• Evidence of viral replication with Hepatitis C virus (HCV), together with evidence of any hepatic fibrosis or inflammation. Such patients should be offered HCV treatment first.

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

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

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

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

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

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