• Men or women age ≥ 18.
• History of effort-induced anginal symptoms and currently experiencing angina at least 3 times per week, despite maximally tolerated doses of antianginal medications, statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and other medications thought to positively impact subjects with CMD.
• Diagnosis of CMD within 180 days prior to the first screening visit based on the following thresholds: coronary flow reserve (CFR) ≤ 2.5, coronary blood flow (CBF) response to acetylcholine ≤ 50%, myocardial perfusion reserve (MPR) or myocardial flow reserve (MFR) 25.
• *CCS class II, III, or IV chronic refractory angina as evaluated by the site.
• No obstructive disease on coronary angiogram within 6 months prior to or during screening. The following is allowed: a coronary artery stenosis less than 40% in the left main coronary artery, or a stenosis less than 50% in any other epicardial coronary artery.
• if subject is of childbearing potential, the subject must have a negative pregnancy test at screening and prior to mobilization and G-CSF treatment, and prior to receiving treatment. The subject agrees to employ adequate birth control measures for the duration of the study. Acceptable methods of birth control are: oral contraceptive tablets, hormonal implant device, hormonal patch, intrauterine device, diaphragm and contraceptive cream or foam, condom with spermicide, partner vasectomy, or abstinence.
• Subject is willing and able to comply with the requirements of the protocol.
• Any cardiovascular medical therapy must be at a stable dose for at least 30 days prior to the first screening visit and must be maintained at that dose throughout the duration of the study; cardiovascular therapy would generally include statins (unless not tolerated), ACE inhibitors, ARBs, beta blockers, calcium channel blockers, and/or ranolazine (unless ineffective or not tolerated).
• Able to provide signed informed consent.

• Myocardial infarction within 90 days prior to consent or between consent and treatment with CLBS16.
• Evidence of obstructive heart disease on screening angiogram or within 6 months prior to consent, including prior CABG at any time or history of PCI within 6 months prior to consent.
• Planned PCI or CABG.
• Diagnosis of other specific cardiac disease including:
  • aortic valve area < 1.0;
  • 3+ mitral regurgitation;
  • 3+ aortic insufficiency;
  • hypertrophic cardiomyopathy;
  • suspected or diagnosed Prinzmetal angina, or if acetylcholine provocation has been performed, significant coronary spasm as defined by more than 70% reduction in vessel diameter in response to acetylcholine;
  • severe myocardial bridging per investigator’s discretion;
  • Any anomalous coronary anatomy which could contribute to the subject’s angina.
• LVEF < 30%.
• Glomerular filtration rate < 30 mL/min/1.73m^2 (MDRD).
• Subject currently uses coumadin, dabigatran, apixaban, rivaroxaban, or edoxaban or plans to use one of these agents during the time frame of the trial.
• Subject has serious hypersensitivity or a history of adverse reaction to G-CSF or apheresis.
• Subject has a known allergy to mouse proteins
• Subject tests positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
• Subject with chronic inflammatory disease or autoimmune disease that has had an acute exacerbation of disease within the last 6 months, or subjects that are on immunosuppressive agents or in a chronic immunosuppressive state.
• Recent history of abuse or current abuser of alcohol or recreational drugs.
• Subject is pregnant or lactating at the time of signing the consent.
• Malignant neoplasm (other than adequately treated non-melanoma skin cancer or in situ cervical carcinoma) within 5 years prior to screening.
• Subject has participated in another clinical study within 90 days prior to signing the informed consent or is scheduled to participate in another clinical study during the course of the study. Observational studies in which the subject did not receive treatment or did not undergo procedures which may compromise this study’s data integrity may be allowable following Sponsor approval.
• History of sickle cell disease.
• Previous treatment with a CD34+ cell-based therapy.
• Any other condition which, in the opinion of the investigator, may preclude the subject from safe participation in the study or compromise data integrity

Eligibility last updated 10/4/21. Questions regarding updates should be directed to the study team contact.

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

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

• Male or female subjects between 28 days and less than 18 years of age, with clinical features that are consistent with a diagnosis of ARPKD.
• Ability for parent/legal guardian to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial. Ability to provide written informed assent from all subjects old enough per local laws to provide assent.

• Premature birth (≤ 32 weeks gestational age) for infants 28 days to < 12 weeks of age.
• Anuria or RRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration or history of kidney transplantation.
• Evidence of syndromic conditions associated with renal cysts (other than ARPKD).
• Abnormal liver function tests including ALT and AST, > 1.2 × ULN (upper limit of normal).
• Has splenomegaly or portal hypertension (HTN).
• Parents with renal cystic disease.
• Receiving chronic diuretic that could not be adjusted after tolvaptan initiation.
• Cannot be monitored for fluid balance. 
• Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator.
• Has or at risk of having significant hypovolemia as determined by investigator.
• Clinically significant anemia, as determined by investigator.
• Platelets < 50000 µL.
• Severe systolic dysfunction defined as ejection fraction < 14%.
• Serum sodium levels < 130 mmol/L or >145 mmol/L.
• Taking any other experimental medications.
• Require ventilator support.
• Taking medications known to induce CYP3A4 (CYP = Cytochrome P).
• Having an infection including viral that would require therapy disruptive to IMP dosing.
• Females who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP.
• Subjects with a history of substance abuse (within the last 6 months).
• Subjects who have bladder dysfunction and/or difficulty voiding.
• Subjects taking a vasopressin agonist (e.g., desmopressin).
• Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy.
• Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (i.e., marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense ribonucleic acid (RNA) therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (i.e., octreotide, sandostatin).
• Received or are scheduled to receive a liver transplant.
• History of cholangitis within the last 6 months.
• Has findings consistent with clinically significant portal hypertension (e.g., varices, variceal bleeding, hypersplenism indicated by thrombocytopenia).

Eligibility last updated 6/2/23. Questions regarding updates should be directed to the study team contact.

• Signed informed consent.
• Either of the following:
  • Completed the full treatment period of the lead-in trial (ZP1848-17111), regardless of treatment adherence; OR
  • Completed the Phase 2 trial (ZP1848-15073).

• Withdrew consent from lead-in or Phase 2 trial.
• Any condition, disease, or circumstance that in the Investigator's opinion would put the patient at any undue risk, prevent completion of the trial, or confounds planned assessments of the trial.
• Use of GLP-1, GLP-2, human growth hormone (HGH), dipeptidyl peptidase-4 (DPP-4) inhibitors, citrulline, somatostatin, or analogs thereof within 3 months.
  • Note: Prior glepaglutide trial drug is allowed.
• Females of childbearing potential, who are pregnant, breast-feeding, intend to become pregnant, or are not using highly effective contraceptive methods. Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.
• An employee of the sponsor or Investigator or otherwise dependent on them.

Additional Exclusion Criteria Applicable for Patients from the Phase 2:

Trial Patients from the ZP1848-15073 trial (Phase 2 trial) must be excluded from this trial if any of the following criteria are met:

• Not having a diagnosis of SBS defined as remaining small bowel in continuity of estimated less than 200 cm [equal to 79 inches] with the latest intestinal resection being at least 6 months prior to Screening;
• Restorative surgery planned in the trial period;
• SBS-related hospitalizations within 30 days prior to screening;
• Not maintaining a stable PS volume for at least 2 weeks.
  • Note: PS volume is considered stable if both of the criteria below are fulfilled:
  • Actual PS usage (volume and content) matches prescribed PS (± 10% deviation in volume is acceptable); and
  • Urine volume is on average ≥ 1 L per day and ≤ 2.5 L per day.
• Not willing to adhere to an individual pre-defined drinking menu during 48-hours measurement periods;
• Not having a colonoscopy performed during Screening (for patients with remnant colon).
  • Note: The results of the colonoscopy must not give rise to any safety concerns. A colonoscopy performed within 6 months prior to Screening and not giving rise to any safety concerns is accepted. For patients with a remnant colon, which is not connected to the passage of foods and is thereby dormant, a computerized tomography (CT) scan or magnetic resonance imaging (MRI) will suffice at the discretion of the Investigator.
• Not being able to separate stool and urine during the 48-hours measurement periods;
• Any history of colon cancer;
• History of any other cancers (except margin-free resected cutaneous basal or squamous cell carcinoma or adequately treated in situ cervical cancer) unless disease-free state for at least 5 years;
• Poorly controlled inflammatory bowel disease (IBD) that is moderately or severely active or having a fistula interfering with the trial assessments;
• Bowel obstruction or recent history of sub-ileal events;
• Human immunodeficiency virus (HIV) positive, acute liver disease, or unstable chronic liver disease;
• Cardiac disease defined as: decompensated heart failure (New York Heart Association [NYHA] Class III-IV), unstable angina pectoris, and/or myocardial infarction within the last 6 months prior to Screening;
• Clinically significant abnormal screening ECG as judged by the Investigator;
• Repeated (2 or more consecutive measurements) systolic blood pressure measurements >180 mm Hg;
• Systemic immunosuppressive therapy that has been introduced or has been unstable within 3 months prior to Screening;
• Unstable biological therapy (e.g., TNF-α (anti-tumor necrosis factor), natalizumab, etc.), including significant changes in doses or switch of drug within 6 months prior to Screening;
• Unstable doses within 2 weeks prior to screening:
  • Antimotility drugs; e.g., loperamide, diphenoxylate, codeine or other opiates;
  • H2 antagonists;
  • Anti-diarrheal agents;
  • Bile acid sequestering agents;
  • Oral glutamine;
  • Proton pump inhibitors;
  • Diuretics;
  • Systemic antibiotics or antibiotics affecting the gastrointestinal tract;
  • Oral rehydration fluids.
• Estimated creatinine clearance (CLcr; by the Cockcroft-Gault formula) < 30 mL/min.;
• Hepatic impairment defined as:
  • Total bilirubin ≥ 2 × the upper limit of normal (ULN); or
  • Aspartate aminotransferase (AST) ≥ 5 × ULN; or
  • Alanine aminotransferase (ALT) ≥ 5 × ULN.

Subjects who meet the following criteria will be eligible to participate in the Long-Term Follow-Up study:

• All adult and pediatric subjects who received at least one GM T cells infusion in a previous Celgene sponsored or Celgene alliance partner sponsored study, and have discontinued, or completed the post-treatment follow-up period in the parent treatment protocol, as applicable.
• Subject (and, parental/legal representative, when applicable) must understand and voluntarily sign an Informed Consent Form/Informed Assent Form prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

• None.

• 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.

• 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.

Screening Period

• Signed written informed consent in accordance to ICH-GCP and national/local regulation before any protocol-related procedures that are not part of normal patient care.
• Female patients ≥ 18 years of age.
• Histologically confirmed high grade, stage IIIC or stage IV (FIGO staging) serous ovarian, fallopian or primary peritoneal carcinoma with abnormal CA-125 at diagnosis.
• Patients who have undergone primary debulking surgery or interval debulking surgery and completed a total of at least 5 cycles of taxane-platinum combination.
  • Note: patients may have received concurrent or maintenance bevacizumab or a PARP inhibitor.
• Patients must have achieved a complete response to therapy, as demonstrated by no residual disease on most recent CT scan and normal CA-125 not increasing by both the following: > 25% from nadir AND ≥ 10 UI/mL from nadir.
• Patient who remains disease free at least 6 months from last prior dose of cytotoxic chemotherapy (maintenance therapy with bevacizumab or a PARP inhibitor is allowed).
• Available tumor tissue, banked from previous abdominal debulking surgery and/or from a core needle biopsy performed at diagnosis if the patient received neoadjuvant chemotherapy, and peripheral blood samples for exome and transcriptome sequencing.

Treatment Period

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at treatment period initiation.
• Patients who have developed an asymptomatic relapse as defined by:
  • Cohort A: CA-125 ≥ 2 times ULN on 2 occasions at least 1 week apart (GCIG criteria) or low volume radiological disease and CA-125 > ULN. Low volume radiological disease is defined as radiologically visible disease excluding intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage;
  • Cohort B: patient asymptomatic with measurable disease, excluding intra-hepatic or splenic metastases, ascites or pleural effusion thought to require drainage, whatever serum CA-125 level and for whom further treatment is not planned within 2 months.
  • Longest diameter on CT-scan must not exceed 2 cm for non-nodal lesions and 2.5 cm in short axis for nodal lesions.
• Adequate hematological, hepatic and renal functions:
  • Hemoglobin ≥ 9.0 g/dL;
  • Neutrophils count ≥ 1.5 x10^9 /L;
  • Lymphocytes count ≥ 0.9 x10^9 /L;
  • Platelets count ≥ 100 x10^9 /L;
  • Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert’s syndrome);
  • Aspartate aminotransferase (AST) ≤ 2.5 x ULN;
  • Calculated creatinine clearance ≤ 45 mL/min using the Cockroft & Gault formula or ≥ 45 mL/min/1.73m² using other methods.
• Patients who received standard maintenance therapy will stop before initiation of TG4050 administration. A free-interval of at least 30 days will be respected before first dosing of TG4050 except for PARP inhibitor (at least 14 days).

Screening Period

• Patient having received any cancer immunotherapy including cancer vaccines, any antibody/drug targeting T cell co-regulatory proteins such as anti-PD1, anti-PDL1 or anti-CTLA-4.
• Patients with other active malignancy ≤ 3 years prior to registration except non-melanoma skin cancer, stage 0 in situ carcinoma and recent early stage papillary thyroid cancer. If there is an history of prior malignancy, patient must not be receiving other specific treatment for their cancer.
• Patient post-organ transplantation, including allogeneic stem cell or bone marrow transplantation. History of blood transfusion within 3 weeks prior to study entry visit.
• Known history of positive testing for Human Immunodeficiency Virus (HIV) or known AIDS (Acquired Immune Deficiency Syndrome).
• Any known allergy or reaction to eggs or attributed to compounds of similar chemical or biological composition to therapeutic vaccines/immunotherapeutic products.
• Positive serology for Hepatis C Virus (HCV) or positive serum Hepatitis B surface antigen (HBsAg) within 3 months prior to or at study entry (tests required).

Treatment Period

• Measurable disease associated with the appearance of symptoms justifying initiation of further treatment.
• Major surgery within 4 weeks prior to treatment start.
• Treatment with another investigational agent within 30 days prior to TG4050 treatment initiation.
• Patients under chronic treatment with systemic corticosteroids or other immunosuppressive drugs for a period of at least 4 weeks and whose treatment was not stopped 2 weeks prior to TG4050 treatment initiation planned date, with the exception of patients with adrenal insufficiency who may continue corticosteroids at physiological replacement dose, equivalent to ≤ 10 mg prednisone daily. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.
• Vaccination for the prevention of infectious diseases with a live vaccine during the four-week period prior to TG4050 treatment initiation planned date. Furthermore, patients should not receive any live vaccine during the period of study treatment administration.
• Patient with any underlying medical condition, that in the opinion of the investigator, could make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety or toxicity of the study treatment.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social circumstances that could limit compliance with study requirements.
• History of myocardial infarction ≤ 6 months.

Eligibility last updated 4/20/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old
• Histological confirmation of melanoma of any mucosal site including (but not limited to) anus/rectum, vulvar/vaginal, sinonasal.
  • NOTE: Melanomas of cutaneous origin and/or ocular origin are ineligible.
• R0 or R1 resection of primary melanoma tumor (no gross disease can be left behind, but microscopically positive margins are acceptable).
• Surgery within ≤ 90 days of registration.
• ECOG Performance Status (PS) ≤ 1.
• The following laboratory values obtained ≤ 14 days prior to registration:
• Hematological
  • Absolute Neutrophil Count (ANC) ≥ 1500/mm^;3
  • Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused);
  • Platelet (Plt) 100,000/mm^3.
• Renal
  • Serum Creatinine ≤ 1.5 x ULN.
• Hepatic
  • Alkaline Phosphatase (Alk Phos) ≤ 1.5 x upper limit of normal (ULN);
  • Total and Direct Bilirubin ≤ 1.5 × (ULN);
  • Aspartate aminotransferase (AST) ≤ 1.5 × ULN.
• Negative pregnancy test done within 7 days prior to registration, for women of childbearing potential only.
  • NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Written informed consent and HIPAA authorization for release of personal health information prior to registration.
  • NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Willing to return to enrolling institution for follow-up.
• Willing to provide archival tissue prior to C1D1 if available and blood samples for correlative research purposes

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and subjects known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Subjects known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 3 years prior to registration.
  • EXCEPTIONS: Malignancies with a very low (< 5%) risk of recurrence such as non-melanotic skin cancer or carcinoma-in-situ of the cervix.
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Active autoimmune disease -including but not limited to:
  • Subjects with a history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease;
  • Subjects with a history of symptomatic autoimmune disease requiring systemic treatment within the past 2 years with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs:
  • rheumatoid arthritis;
  • systemic progressive sclerosis (scleroderma);
  • systemic lupus erythematosus;
  • psoriasis;
  • autoimmune vasculitis (e.g., Wegener’s Granulomatosis);
  • CNS or motor neuropathy considered of autoimmune origin (e.g., GuillainBarre Syndrome and Myasthenia Gravis, multiple sclerosis).
    • EXCEPTION: autoimmune conditions that are only requiring replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Any radiation within 2 weeks prior to study initiation. Neoadjuvant and adjuvant radiation are allowed, but must be completed > 2 weeks prior to registration.
• Any prior systemic therapy for melanoma (chemotherapy, immunotherapy, targeted therapy).
• Women of childbearing potential (WOCBP) must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent until 5 months after the last dose of study drug. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Examples include: intrauterine device (IUD), vasectomy of a female subject’s male partner, contraceptive rod implanted into the skin, or use of two of the following: diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), hormonal contraceptive.

*Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

• NOTE: Male subjects are not required to utilize contraception. The study regimen is not genotoxic and systemic concentrations sufficient to produce a risk of fetal toxicity are not expected in WOCBP partners from exposure to a male participant’s seminal fluid.
• Pregnant or breastfeeding.
  • NOTE: breast milk cannot be stored for future use while the mother is being treated on study.

• Male or female, aged ≥ 18 years.
• Confirmed diagnosis of:
  • For the monotherapy cohorts: Metastatic or unresectable BC, NSCLC, CRC, ovarian cancer, or acral melanoma that is refractory to standard therapy or for which no standard therapy exists. Participants who are considered intolerant of or ineligible for standard therapy(ies), as well as participants who have been offered but refused standard therapy(ies), may also be eligible;
  • For the pembrolizumab combination therapy cohort: Metastatic or unresectable NSCLC, CRC (only MSI-H or dMMR), melanoma (with the exception of uveal melanoma), HCC, HNSCC, ESCC, or UC with prior or ongoing pembrolizumab treatment and have progressed or have achieved stable disease and who, in the judgment of their treating physicians, could benefit from the addition of ATRC-101 to improve or maintain their response:
  • Individuals with BRAF mutant melanoma must have received BRAF inhibitors alone or in combination with a MEK inhibitor, if indicated;
  • Individuals with NSCLC should have received platinum-based therapy unless contraindicated.
  • For the PLD combination therapy cohort: Metastatic or unresectable high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum resistant, defined as progression during or within 6 months of the last dose of platinum-based chemotherapy OR BC that is refractory to other standard therapies.
• Measurable disease based on RECIST v1.1, as assessed by the local site investigator/radiologist. Lesions situated in an area treated with radiation or other locoregional therapy are considered measurable only if the progression has been demonstrated in such lesions following loco-regional therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate organ and marrow function (i.e., without chronic, ongoing growth factor or transfusion support) at Screening as defined by the following laboratory parameters:
  • Absolute neutrophil count (ANC) ≥ 1000/µL;
  • Absolute lymphocyte count (ALC) ≥ 500/ µL;
  • Platelet count ≥ 75,000/µL;
  • Hemoglobin ≥ 9.0 g/dL;
  • PT/INR, aPTT ≤ 1.5 x ULN unless participant is receiving a stable dose of therapeutic anticoagulation;
  • Albumin ≥ 3.0 g/dL;
  • Creatinine clearance or eGFR ≥ 30 mL/min as estimated by the Cockcroft-Gault equation;
  • AST/ALT ≤ 2 x ULN. If documented liver metastases, then ≤ 5 x ULN;
  • Bilirubin ≤ 2 x ULN; or bilirubin ≤ 3 x ULN if due to Gilbert’s or Crigler-Najjar disease.
• Available representative tumor specimens in paraffin blocks (preferred) or ≥ 20 unstained slides, with an associated pathology report, obtained after last systemic anti-cancer therapy and within 60 days prior to the planned first dose of investigational product. If fewer than 20 unstained slides are available, a discussion with the Medical Monitor is required prior to enrollment. If an archived sample is not available, participant must have a tumor that is amenable to biopsy without unacceptable risk of a major procedural complication and consent to have a tumor biopsy. Tumor lesions used for biopsy should not be lesions used as RECIST 1.1 target lesions unless there are no other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion must be ≥ 2cm in longest diameter:
  • For the pembrolizumab combination therapy cohort:
  • A biopsy collected within 60 days of the planned first dose of investigational product while the participant is receiving pembrolizumab is acceptable.
• Women of childbearing potential (WOCBP) and fertile males with partners who are WOCBP must use highly effective contraception (per CTFG 2014) from first dose and through 90 days after final dose of investigational product.
• Willing and able to provide written informed consent and able to comply with all trial procedures.

• Disease that is suitable for local therapy administered with curative intent.
• Malignant disease other than the malignancy to be investigated in this trial within the last 5 years with the exception of basal or squamous cell carcinoma of the skin OR curatively treat in situ disease.
• Autoimmune disease requiring systemic treatment (e.g., with disease modifying agents, corticosteroids, or immunosuppressive drugs) in the past 2 years. Hormone replacement therapy (e.g., insulin, thyroxine, and replacement-dose hydrocortisone) is not considered systemic treatment.
• Active or prior paraneoplastic neurologic disorder of the central nervous system (CNS).
• Prior allograft.
• Clinically significant cardiovascular disease; e.g., cerebral vascular accident/stroke or myocardial infarction, within 6 months prior to the first dose of investigational product, unstable angina, congestive heart failure (New York Heart Association ≥ Class III), or unstable cardiac arrhythmia requiring medication.
• Presence of active, symptomatic, or untreated CNS metastasis; or CNS metastasis that requires local directed therapy or increasing doses of corticosteroids within the 2 weeks prior to the planned first dose of investigational product. Individuals with treated and/or asymptomatic CNS disease may be enrolled if neurologically stable over the prior 2 weeks (and after consultation with the Medical Monitor).
• HIV infection with an AIDS-defining  opportunistic infection within the past 12 months or with a CD4+ T cell count < 350/µL
• Hepatitis B surface antigen (HBsAg) positive OR anti-Hepatitis B core (anti-HBc) positive and HBV viral load above the lower limit of quantification.
• Hepatitis C antibody positive with HCV viral load greater than or equal to the lower limit of quantification.
• Infection requiring intravenous antibacterial, antiviral, or antifungal therapy within 2 weeks prior to the planned first dose of investigational product.
• Ongoing ≥ Grade 2 toxicity(ies) due to a previously administered anticancer agent with the following exceptions:
  • Grade 2 neuropathy or alopecia;
  • For the monotherapy cohorts: Grade 2 immune-related endocrinopathy attributed to a checkpoint inhibitor and controlled with hormone replacement alone.
• Treatment with biological agents (including monoclonal antibodies) within 28 days of the planned first dose of investigational product with the following exception:
  • For the pembrolizumab combination therapy cohort: Pembrolizumab treatment within 28 days of the planned first dose of investigational product.
• Treatment with radiation, chemotherapy or anticancer small molecule therapy within 14 days or 5 half-lives (whichever is longer) prior to the planned first dose of investigational product. Treatment with nitrosoureas or mitomycin C require a 42-day washout prior to the planned first dose of investigational product.
• Receipt of any investigational drug or device not otherwise specified above within 28 days or 5 half-lives (whichever is longer) prior to the planned first dose of investigational product.
• Pregnant or breastfeeding; negative pregnancy status in WOCBP must be confirmed by serum pregnancy test at Screening.
• History of ≥ Grade 3 infusion-related reaction associated with antibody administration; or:
  • For the monotherapy cohorts: Known allergy/intolerance to ATRC-101 or its excipients;
  • For the pembrolizumab combination therapy cohort: Known allergy/intolerance to ATRC-101, pembrolizumab, or their excipients.
• Major surgery or significant traumatic injury occurring within 28 days prior to the planned first dose of investigational product. If major surgery occurred > 28 days prior to Cycle 1-Day 1, individual must have recovered adequately from the toxicity and/or complications from the intervention prior to Cycle 1-Day 1.
• Prior treatment with ATRC-101.
• Intercurrent illness that is either life-threatening or of clinical significance such that it might limit compliance with trial requirements, or in the Investigator’s assessment would place the participant at an unacceptable risk for participation.
• Receipt of a live vaccine within 30 days of planned Cycle 1-Day 1. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed. Intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed.

For the pembrolizumab combination therapy cohort ONLY:

• Experienced ≥ Grade 3 or higher immune related adverse events while on immunotherapy prior to enrollment.
• Have not recovered from ≥ Grade 2 immune related adverse events attributed to immunotherapy prior to enrollment.
• NSCLC with epidermal growth factor receptor (EGFR) or anaplastic lymphoma receptor tyrosine kinase (ALK) genomic tumor alterations.
• Isolated intracranial relapse.
• Interstitial lung disease or active, non-infectious pneumonitis.
• Signs and symptoms consistent with clinically significant, decreased pulmonary function: (1) blood saturation oxygen level (SpO2) < 90% at rest on room air; (2) dyspnea at rest (CTCAE ≥ Grade 3) or required supplemental oxygenation within 14 days prior to the planned first dose of investigational product.
• Ongoing immune-related toxicity or immune-related toxicity at any time requiring systemic corticosteroids.

Key

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

Eligibility last updated 9/29/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 7/20/22. Questions regarding updates should be directed to the study team contact.

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

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

• Males and females, at least 40 years of age, capable and willing to provide informed consent
• Patient must have received a diagnosis of COVID-19 infection within the last 24 hours
• Outpatient setting (not currently hospitalized or under immediate consideration for hospitalization)
• Patient must possess at least one of the following high-risk criteria:
  • 70 years or more of age, obesity (BMI ≥ 30 kg/m2)
  • Diabetes mellitus
  • Uncontrolled hypertension (systolic blood pressure ≥150 mm Hg)
  • Known respiratory disease (including asthma or chronic obstructive pulmonary disease)
  • Known heart failure
  • Known coronary disease
  • Fever of ≥38.4°C within the last 48 hours
  • Dyspnea at the time of presentation
  • Bicytopenia
  • Pancytopenia
  • The combination of high neutrophil count and low lymphocyte count
• Female patient is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine device (IUD)) throughout the study and for 30 days after study completion
• Patient must be able and willing to comply with the requirements of this study protocol.

• Patient currently hospitalized or under immediate consideration for hospitalization
• Patient currently in shock or with hemodynamic instability
• Patient with inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhea or malabsorption
• Patient with pre-existent progressive neuromuscular disease
• Estimated Glomerular filtration rate (eGFR), using the MDRD equation for all subjects being considered for enrollment, with a cut-off of < 30 mL/m in/1.73m2
• Patient with a history of cirrhosis, chronic active hepatitis or severe hepatic disease
• Female patient who is pregnant, or breast-feeding or is considering becoming pregnant during the study or for 6 months after the last dose of study medication
• Patient currently taking colchicine for other indications (mainly chronic indications represented by Familial Mediterranean Fever or gout)
• Patient with a history of an allergic reaction or significant sensitivity to colchicine
• Patient undergoing chemotherapy for cancer
• Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study.

Inclusion criteria:

1. Are ≥ 18 years of age at screening.

2. Have a clinical diagnosis of TED associated with active, moderate to severe TED with a
CAS ≥ 4 in either eye at screening and Baseline.

3. Have moderate to severe active TED, as defined by European Group on Graves'
Orbitopathy (EUGOGO) guidelines.

4. Have onset of active TED within 12 months prior to screening.

5. Have documented evidence of detectable anti-TSHR-Ab at screening.

6. Are not expected to require immediate surgical intervention and are not planning
corrective surgery/irradiation or medical therapy for TED during the course of the
study.

7. Are euthyroid with the baseline disease under control or have mild hypo- or
hyperthyroidism.

Additional inclusion criteria are defined in the protocol.

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

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

• Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic or is surgically unresectable. 
• Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area or in an area subjected to other loco-regional therapy are considered measureable if progression has been clearly demonstrated in the lesion. 
• Documentation of an FGFR1-3 gene mutation or translocation. 
• Objective progression after at least 1 prior therapy and no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit. 
• Eastern Cooperative Oncology Group performance status 0 to 2.
• Baseline archival tumor specimen (if < 12 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis. 
• Willingness to avoid pregnancy or fathering children.

• Prior receipt of a selective FGFR inhibitor in the past 6 months. 
• Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. 
• Cannot be a candidate for potentially curative surgery. 
• Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. 
• Radiation therapy administered within 2 weeks of enrollment/first dose of study treatment.
• Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). 
• Known additional malignancy that is progressing or requires active treatment. 
• History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues.
• Clinically significant or uncontrolled cardiac disease. 
• Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment within 2 weeks before enrollment (participants with asymptomatic chronic infections on prophylactic treatment are allowed). 
• Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as elevated transaminases or cirrhosis; chronic HBV/HCV infection with no cirrhosis and no elevated transaminases is allowed). 
• Known HIV infection. 
• Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or five half-lives (whichever is longer) before the first dose of study drug/treatment. 
• Women who are pregnant or breastfeeding.

• High-risk disease defined as an IPI score of 4 or 5 at initial diagnosis.
• Histologically confirmed LBCL based on 2016 World Health Organization (WHO) classification by local pathology lab assessment, including one of the following:
  • Diffuse large B-cell lymphoma, NOS;
  • High-grade B-cell lymphoma (HGBL) (including HGBL with MYC and BCL2 and/or BCL6 rearrangements (DHL/THL) based on FISH analysis, and HGBL-NOS);
    • Note: Transformed DLBCL from follicular lymphoma or from marginal zone lymphoma is eligible if no prior treatment with anthracycline-containing regimen.
• Ann Arbor Stage III or IV disease.
• Have received only 1 cycle of R-chemotherapy.
• At least 1 measurable lesion per the Lugano Classification {Cheson 2014} on anatomical imaging such as computed tomography (CT) imaging (functional imaging such as PET may not be used to identify a measurable lesion). A measurable lesion is defined as greater than 1.5 cm LDi for lymph node and greater than 1.0 cm LDi for extranodal lesion.
• Adequate tumor biopsy specimen available for central pathology review (detailed sample collection requirement is in central pathology laboratory manual).
• Age 18 years or older.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of randomization;
  • Note: ECOG > 1 at diagnosis is acceptable.
• Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function as indicated by:
  • Absolute neutrophil count (ANC) ≥ 1000/μL;
  • Platelet count ≥ 75,000/μL;
  • Absolute lymphocyte count ≥ 100/μL;
  • Creatinine clearance (as estimated by any local institutional method) ≥ 60 mL/minute;
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 x ULN if documented liver involvement of lymphoma;
  • Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s Syndrome or documented LBCL liver or pancreatic involvement where ≤ 3.0 times the ULN;
  • Left ventricular ejection fraction (LVEF) ≥ 50% and no evidence of clinically significant pericardial effusion, and no clinically significant abnormal electrocardiogram (ECG) findings;
  • No evidence of Grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] 5.0) or greater pleural effusion or ascites (subjects with Grade 1 ascites or pleural effusion are eligible);
  • Baseline oxygen saturation > 92% on room air.
• Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential).

• Any prior treatment for LBCL other than the 1 cycle of R-chemotherapy.
• The following WHO 2016 subcategories by local assessment:
  • T-cell/histiocyte-rich LBCL;
  • Primary DLBCL of the CNS;
  • Primary mediastinal (thymic) LBCL;
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma;
  • Burkitt lymphoma.
• History of severe immediate hypersensitivity reaction attributed to aminoglycosides.
• Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple bacterial infections are permitted if responding to active treatment and after consultation with the Kite medical monitor.
• History of acute or chronic active hepatitis B or C infection. If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a CD4 count > 200 cells/uL.
• Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are permitted.
• Presence of detectable cerebrospinal fluid (CSF)-malignant cells, brain metastases, or a history of central nervous system (CNS) involvement of lymphoma.
• Presence of CNS disorder such as dementia, autoimmune disease with CNS involvement, cerebral edema with confirmed structural defects by appropriate imaging, or seizure disorders requiring active anticonvulsive medication. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrollment.
• Presence of cardiac atrial or ventricular lymphoma involvement.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months before enrollment.
• Presence of primary immunodeficiency A.
• History of autoimmune disease (eg, Crohn’s disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
• History of non-line associated, clinically significant (CTCAE 5.0 Grade 2 or greater) deep vein thrombosis or pulmonary embolism requiring therapeutic anticoagulation within 6 months of randomization.
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study, including the lymphodepletion chemotherapy (cyclophosphamide or fludarabine).
• Live vaccine ≤ 6 weeks before the planned start of the lymphodepletion chemotherapy regimen.
• Females of childbearing potential who are pregnant or breastfeeding (due to potentially dangerous effects of the preparative chemotherapy on the fetus or infant).
• Not willing to practice birth control from the time of consent through at least 6 months after the last dose of axicabtagene ciloleucel or SOCT 20) In the investigator’s judgment, the subject is unlikely to complete all study-specific visits or procedures, including follow-up visits, or comply with the study requirements for participation.

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

• Male or female.
• 12 years or older.
• Within 72 hours before randomization, blood culture positive for S. aureus determined by rapid diagnostic test or conventional method, or Gram stain showing Gram-positive cocci in clusters and either positive tube coagulase test or positive latex slide agglutination test from blood culture specimens.
  • Note: The 72-hour time period starts at the time the specimen is collected for blood culture. Any S. aureus-positive blood culture collected within the 72 hours before randomization can be used to support enrollment of the patient.
• At least two of the following signs or symptoms attributable to S. aureus BSI/IE within approximately 24 hours before randomization. If more than one measurement is taken within approximately 24 hours before randomization, the most abnormal value is used for inclusion:
  • Shortness of breath;
  • Sweating;
  • Chills and/or rigors;
  • Fatigue;
  • Confusion;
  • Pain associated with metastatic foci;
  • Fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) or hypothermia (oral temperature equivalent 10,000/µL) [CTCAE 2017], leukopenia (WBC 10% immature neutrophils [bands] regardless of total peripheral WBC);
  • Tachycardia (heart rate >100 bpm)
  • Tachypnea (respiratory rate >20 breaths/min);
  • Hypotension (systolic blood pressure < 90 mmHg).
• Patient must have:
  • Known or suspected R-IE (involvement of pulmonic and/or tricuspid valve[s]) based on Modified Duke Criteria (defined in protocol); or
  • Known or suspected complicated S. aureus BSI, demonstrated as one or more of the following:
  • Blood culture positive for S. aureus on more than one day;
  • Clots in the vein at the catheter site seen on ultrasound;
  • Signs or symptoms of metastatic foci of S. aureus infection (e.g., splenic abscess, deep tissue abscess not associated with open wound or other local source of infection, septic pulmonary emboli) or hematogenous seeding (e.g., of the renal system evidenced by S. aureus bacteriuria [in absence of other source such as indwelling ureteral catheter], septic arthritis, osteomyelitis) confirmed by physical examination, imaging, and/or culture (as described in the study procedures sections of the protocol);
  • Persistent fever (oral temperature equivalent ≥ 38.0°C [≥ 100.4°F]) for 72 hours or more;
  • Met criteria for sepsis or septic shock using the Sequential (sepsis-related) Organ Failure Assessment (SOFA) score (definition in protocol [adapted from Singer 2016]) during the time of diagnosis/presumptive diagnosis of BSI. If the SOFA score is the only criteria for complicated S. aureus BSI that is met, contact the Medical Monitor prior to randomization;
  • Significantly immunocompromised:
  • AIDS (HIV positive with an AIDS-defining condition or a CD4 count < 200 cells/mm³);
  • Severe leukopenia defined as absolute neutrophil count (ANC)  < 500 cells/mL for ≥ 3 days in the 7 days prior to the qualifying blood culture;
  • Post organ-transplantation including autologous bone marrow transplantation;
  • On treatment for active graft vs. host disease;
  • On immunosuppressive therapy (e.g., ≥15 mg of prednisone or equivalent for more than 5 days, biologics such as infliximab, monoclonal antibodies such as daclizumab, methotrexate, cyclophosphamide, or similar agents);
  • On myelosuppressive chemotherapy; or
  • At least one of the following risk factors for complicated S. aureus BSI:
  • Preexisting right-sided valvular heart disease;
  • Surgery (e.g., orthopedic, cardiothoracic, or intraabdominal surgery) within the previous 30 days that puts the patient at risk for nosocomial bacteremia;
  • Extravascular foreign material.
  • Note: Catheters including ports, AV fistulas and related dialysis access points are considered intravascular foreign material;
  • Hemodialysis.
• Patient is not pregnant or breastfeeding and meets one of the following criteria:
  • A female patient who is not of childbearing potential is eligible without requiring the use of contraception. This includes female patients who have not undergone menarche or who are documented to be surgically sterile (e.g., hysterectomy, or removal of both ovaries, or tubal ligation) or postmenopausal (i.e., amenorrhea >1 year and follicle stimulating hormone [FSH] >40 mIU/mL) with a negative pregnancy test. FSH and pregnancy testing is not required in postmenopausal females with amenorrhea for > 2 years;
  • Female patients of childbearing potential and male patients with partners of childbearing potential must agree to remain abstinent* or use 2 methods of contraception and refrain from donating sperm (male patients) from screening through 30 days after receiving the study drug.
  • *Abstinence is defined as refraining from heterosexual intercourse from screening through 30 days after receiving the study drug; the Investigator will consider whether abstinence is consistent with the preferred and usual lifestyle of the patient. Acceptable methods of contraception include either:
  • Hormonal contraception (injection, implant, pill, patch, or vaginal ring) and a condom or diaphragm with spermicide; or
  • Intrauterine device (IUD) and a condom or diaphragm;
  • A male patient who is not of reproductive potential is eligible without requiring the use of contraception. This includes males who have undergone a successful vasectomy, defined as (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.
• Willing and able to provide written informed consent or assent. If the patient is not able to provide written informed consent or assent, written informed consent may be provided by the patient’s legally acceptable representative as permissible based on local laws and regulations. For patients 12 to < 18 years of age, written informed consent from the patient’s parent/guardian or other legally acceptable representative will be obtained according to the site’s IRB requirements. For emancipated minors, written informed consent will be obtained according to the site’s IRB requirements.

Exclusion Criteria:

• Previously received exebacase.
• Known or suspected left-sided IE (involvement of mitral and/or aortic valve[s]) based on Modified Duke Criteria (defined in protocol). Note: In patients that have clinical findings suggestive of L-IE (new murmur, worsening cardiac function, and/or peripheral or central nervous embolic phenomenon), a TEE will be performed before randomization to rule out mitral and/or aortic valve vegetation(s) or the patient will be excluded from the study.
• Treatment with any potentially effective systemic anti-staphylococcal antibiotic for more than 72 hours within 7 days before randomization.
• Exception:  Documented S. aureus resistance to the prior systemic antibiotics and/or persistent S. aureus-positive blood cultures while on the systemic antibiotics.
• Current or planned treatment within the 14 days after randomization with dalbavancin or oritavancin.
  • Note:  Patients who are receiving teicoplanin, linezolid, telavancin, beta-lactam/beta-lactam inhibitors (e.g., piperacillin-tazobactam), carbapenems, fourth- or fifth-generation cephalosporins (e.g., cefepime, ceftaroline fosamil), and/or sulfamethoxazole/ trimethoprim are eligible for the study provided that treatment is switched to a protocol-specified appropriate SoCA (appropriate SoCA includes daptomycin and vancomycin for MRSA and semi-synthetic penicillins [e.g., nafcillin, oxacillin, cloxacillin, flucloxacillin] and first-generation cephalosporins [e.g., cefazolin] for MSSA;
  • Daptomycin or vancomycin may be used for patients with MSSA with a known history of beta-lactam allergy or other reason that beta-lactam cannot be used);
  • Patients with persistent S. aureus bacteremia for which ceftaroline fosamil or other nonprotocol recommended antibiotic (e.g., rifampin, gentamicin, other beta lactam) has already been added to a protocol-recommended SoCA prior to randomization, the patient may remain on the non-protocol recommended antibiotic (plus SoCA) after randomization, if approved by the Medical Monitor;
  • Vancomycin or daptomycin used in combination with beta-lactams has not been shown to offer benefit and may increase the risk of kidney injury [Tong 2020]; therefore, this combination should not be used.
• Presence of any removable or surgically managed infection source (e.g., intravascular catheter, abscess) that will not be removed or debrided based upon standard medical practice within approximately 72 hours after randomization.
  • Note: Other hemodialysis access types (i.e., AV fistulas or AV grafts) and surgically managed infection sources that are known or suspected to be infected will be evaluated for removal/replacement, if clinically feasible. If removable/ debridement is not feasible based on standard medical practice, the patient should be discussed with the Medical Monitor.
• Presence of prosthetic valve or cardiac valve support ring, or presence of known or suspected infected orthopedic hardware, prosthetic joint, or cardiac device (e.g., implantable cardioverter defibrillator [ICD], permanent pacemaker).
  • Note: Patients who have S. aureus bacteremia after the removal of infected hardware or cardiac device may be included in the study.
• Known or suspected brain abscess or meningitis.
• Patient with BOTH asplenia and creatinine clearance (CrCl) < 60 mL/min including those on dialysis (risk for reduced ability to catabolize exebacase).
  • Note: CrCl will be calculated by Cockcroft-Gault formula (provided in protocol) using ideal body weight in patients with BMI ≥ 30 kg/m^2 and serum creatinine result obtained locally.
• Patient receiving continuous renal replacement therapy (CRRT) within 4 hours prior toat the time of dosing and/or within 248 hours after dosing.
• Known polymicrobial BSI (i.e., more than one pathogen in the blood).
  • Note: Culture results that include organisms that are considered contaminants do not exclude the patient.
• Patient with known, ongoing systemic infection caused by other bacterial pathogen(s) (i.e., other than S. aureus) and/or fungal pathogen(s) and/or patient who has a known positive coronavirus disease 2019 (COVID-19) diagnostic test at the time of screening. Patients who previously had COVID-19 and are COVID-19-negative by diagnostic test are eligible for enrollment. Note: COVID-19 testing should be performed as clinically indicated in accordance with local standard medical practice.
• Patient is not expected to survive through Day 14 of the study due to underlying comorbidity (e.g., terminal end-stage cancer) and/or patient has an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of > 2530.
• Patient participated or plans to participate in another interventional investigational drug, device, or diagnostic trial involving administration of an investigational agent within 30 days or 5 half-lives of investigational drug, whichever is longer, prior to or during the study.
• Other comorbid condition or laboratory abnormality that would, in the opinion of the Investigator, pose a safety risk for the patient to participate or pose a risk to the patient’s ability to complete the study.
• Patient is employed by the Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority Log) or is a first degree relative of a person employed by the Sponsor or a member of the investigational site study team (i.e., on the Delegation of Authority Log). Patient is institutionalized by administrative or court order.
• Patient is not willing or able to comply with the protocol requirements.

Eligibility last updated 10/20/21. Questions regarding updates should be directed to the study team contact.

• Provisions of signed and dated informed consent form.
• Patient is 18 years of age and older.
• Patient has a diagnosis of Stage 3 PC cytologically or pathologically confirmed per American Joint Committee on Cancer (AJCC) staging criteria.
• Patient 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 SOC.
• Patient has received 3 months of SOC per each participating institution’s guidelines.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Patient has an American Society of Anesthesiologists (ASA) classification of physical health status of 1, 2, 3 or 4.
• Patients at IRE sites who are deemed eligible for IRE and receive ablation using the NanoKnife System.
• Patient shows no evidence of disease progression based on NCCN guidelines after completing three (3) months of SOC.

• Participation in an interventional trial for pancreatic cancer during the study data collection period.
• Pregnant or lactating patients 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.
• Patients who are unable to tolerate general anesthetic with full skeletal muscle blockade.
• Patients 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.

• Signed informed consent must be obtained prior to participation in the study.
• Age ≥ 18 years at the date of signing the informed consent form (ICF).
• Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as:
  • age ≥ 75;
  • ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%);
  • moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN);
  • renal impairment (eGFR ≥ 30 ml/min/1.73m^2 to 45 30 ml/min/1.73m^2); or
  • any other comorbidity (to be documented in the CRF) that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Novartis Medical Monitor before study enrollment.
• Not planned for hematopoietic stem-cell transplantation (HSCT).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3.
• AST and ALT ≤ 3 × upper limit of normal (ULN).
• Total bilirubin ≤ 3.0 × ULN (except in the setting of isolated Gilbert syndrome, in which case higher total bilirubin is allowed provided that conjugated bilirubin is ≤ 3.0 x ULN).
• Estimated Glomerular Filtration Rate (eGFR) ≥ 30 mL/min/1.73 m^2 (estimation based on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)
• Subject is able to communicate with the investigator, and has the ability to comply with the requirements of the study procedures.
• WBC < 25 x10^9 /L (may be reduced with leukopheresis or hyroxyurea).

• Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine. Previous treatment for AML, MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera, with the exception of hydroxyurea, growth factors, and supportive care ruxolitinib.
• Prior exposure to TIM-3 directed therapy.
• Subjects with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA and patients with AML secondary to Down's syndrome.
• Subjects with CNS leukemia or neurologic symptoms suggestive of CNS leukemia (unless CNS leukemia has been excluded by a lumbar puncture).
• Subjects with concurrent or prior malignancy, except:
  • subject with history of MDS, myelofibrosis, essential thrombocythemia, or polycythemia vera;
  • subject with history of adequately treated malignancy for which the subject has been disease free (absence of residual disease) for at least 1 year and if no anticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) is ongoing or required during the course of the study. Patients who are receiving adjuvant therapy such as hormonotherapy are eligible.
• History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients.
• Any concurrent severe and/or uncontrolled medical condition; e.g., active uncontrolled infection or severe infectious disease requiring parenteral antibacterial, antiviral or antifungal therapy (such as severe pneumonia, meningitis, or septicemia).
• Active autoimmune disease requiring systemic therapy (e.g., corticosteroids).
• Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment (C1D1).
• Current use, or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy.
• Live vaccine administered within 30 days prior to the first day of study treatment (C1D1).
• Cardiac or cardiac repolarization abnormality, including but not limited to any of the following:
  • History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment;
  • QTcF > 470 ms at screening (based on mean of triplicate ECG), long QT syndrome or family history of unexplained cardiac death;
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block);
• HIV infection not controlled by standard therapy and/or with known history of opportunistic infection. For countries where HIV status is mandatory: HIV status will be tested during screening using a local test.
• Active Hepatitis B (HBV) or Hepatitis C (HCV) infection. Subjects whose disease is controlled under antiviral therapy should not be excluded.
• Other co-morbidity that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
• Sexually active males unless they use a condom during intercourse while taking azacitidine and for 3 months after stopping this drug. They should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. In addition, male participants must not donate sperm for the time period specified above.
• Subject is pregnant or breastfeeding.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 30 days after the last dose of venetoclax, 90 days after the last dose of azacitidine (or as per their respective local labels, whichever is longer) and 150 days after the last dose of MBG453. It is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method. Highly effective contraception methods include:
  • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment;
  • Male sterilization (at least 6 months prior to screening/baseline). For female subjects on the study the vasectomized male partner should be the sole partner;
  • Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
• In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had over 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms) in the absence of other medical justification or have had surgical bilateral oophorectomy (with or without hysterectomy) or bilateral tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

Eligibility last updated 11/4/21. Questions regarding updates should be directed to the study team contact.

• Are ≥ 18 years of age at the time of signing the informed consent.
  • In Japan, if a patient is < 20 years, the written informed consent from his/her parent or guardian will be required in addition to the patient’s written consent.
• Participants must have measurable or non-measurable but evaluable disease assessed by the Investigator. Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).
• 3. Availability of tumor material (< 6 months old) adequate for biomarker analysis is mandatory for all participants and central laboratory confirmation is required. For participants enrolled in the safety run-in, PD-L1 expression will be tested retrospectively by a central laboratory. For participants enrolled in the expansion part of the study, PD-L1 expression must be tested by the central laboratory and results available before randomization. Only results from the central laboratory testing will be used for randomization and if PD-L1 status is non-evaluable, the participant is not eligible for this study. Tumor samples obtained by endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies, and surgical specimens that are < 6 months old and adequate for biomarker analysis are acceptable. Biopsies obtained by fine needle aspiration are not acceptable.
• Participants with tumor harboring an EGFR sensitizing (activating) mutation, ALK translocation, ROS-1 rearrangement are eligible. These tests are not required for enrollment in the study.
• Participants with ongoing post-obstructive pneumonia due to the tumor are eligible.
• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease):
  • When pleural fluid is visible on both the CT scan and on a chest x-ray, a thoracentesis is required to confirm that the pleural fluid is cytologically negative;
  • Participants with exudative pleural effusions are excluded, regardless of cytology;
  • Participants with effusions that are minimal; i.e., are too small to safely tap are eligible.
• Participants must be at least 3 weeks from prior thoracotomy (if performed).
• Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) ≥ 1.2 liters or ≥ 50% of predicted normal volume measured within 3 weeks prior to randomization. If participants do not meet the above criteria, treatment with inhaled steroids and bronchodilators can be initiated if clinically indicated and eligibility can be reassessed after 1-2 weeks.
• ECOG performance status of 0 to 1 at Screening and on the day of first dose.
• Life expectancy ≥ 12 weeks.
• Have adequate organ function as indicated by the following laboratory values:
  • Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL;
  • Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase (AST) level ≤ 3.0 × ULN, an alanine aminotransferase (ALT) level ≤3.0 × ULN and alkaline phosphatase ≤ 2.5 ULN;
  • Adequate renal function defined by creatine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min for participant with Cr > 1.5 × ULN (GFR can also be used).
    • Note: CrCl  should be calculated per institutional standard. If no local guideline is available, CrCl should be calculated using the Cockcroft-Gault Method:
    • CrCl = ((140-age) * weight (kg) * (0.85 for females only)) / (72 * creatinine).
  • Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
  • Male Participants:
    • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention
    • Refrain from donating sperm; PLUS, either:
      • Abstain from intercourse with a WOCBP;
        • OR
      • Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
  • Female Participants:
    • Are not pregnant or breastfeeding, and at least one of the following conditions applies:
      • Not a WOCBP.
        • OR
      • If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
        • Before the first dose of the study intervention(s), if using hormonal contraception:
        • Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses; OR
        • Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay.
        • During the intervention period.
      • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e., after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 4 months after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period.
    • Have a negative pregnancy test, as required by local regulations, on W1D1 before the first dose of study intervention.
    • Additional requirements for pregnancy testing during and after study intervention are in SoA.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
• Can give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

• Participants with mixed small cell with non-small cell lung cancer histology.
• Greater than minimal, exudative, or cytologically positive pleural effusions.
• Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug.
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
• History of organ transplant that requires therapeutic immunosuppression.
• Significant acute or chronic infections including, among others:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in Screening, however participant refuses testing, discuss with Medical Monitor to assess eligibility. (Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in Screening or while on study, a site must consent the participant for HIV testing as per local standard guidance);
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA, or HBV core antibody positive alone with reflex to positive HBV DNA, or positive HCV antibody with reflex to positive HCV RNA) at Baseline. Discuss with the Medical Monitor if history of HBV or HCV  infection is known. If medically indicated, participants infected with HBV must be treated and on a stable dose of antivirals (e.g, entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at study entry and with planned monitoring and management according to appropriate labeling guidance. Participants on active HCV therapy at study entry must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities (must meet criteria above) and with planned monitoring and management according to appropriate labeling guidance. HBV and/or HCV viral titers must be monitored according to SoA in these participants.
  • Participants with active tuberculosis (history of exposure or history of positive tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, active uveitis or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Known clinical history of tuberculosis, lung sarcoidosis and Interstitial Lung Diseases.
• History of another primary malignancy within 3 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ, e.g., cancer of the cervix in situ, superficial bladder cancer. History of other localized malignancies treated with curative intent needs to be discussed with the Medical Monitor.
• Uncontrolled neuropathy Grade 2 or greater regardless of cause.
• Significant hearing loss and participants unwilling to accept potential for further hearing loss (Investigator should consider treating the participant with carboplatin/paclitaxel).
• Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as anti-PD-(L)1, or anti-CTLA-4 antibody.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the cCRT for locally advanced NSCLC is allowed.
• Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), OR is receiving systemic steroid therapy < 3 days prior to the first dose of study intervention or receiving any other form of immunosuppressive medication. Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at low doses (typically ≤ 10 mg of prednisone or equivalent per day). Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy. Corticosteroid use on study as a premedication for IV contrast allergies/reactions (related to scans) is allowed and must be documented. This must be discussed with Medical Monitors for clinical indications in which participants may require a higher dose. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes Type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.  Consult Medical Monitor for other autoimmune diseases.
• Receipt of live attenuated vaccination within 30 days of receiving study drug.
• Use of a prohibited concomitant drug within 4 weeks randomization.
• Known severe hypersensitivity (Grade ≥ 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) to study interventions or any components in their formulations, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma).
• Participation in another clinical study with an investigational product within the last 4 weeks.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• ≥ 10% weight loss within the past month.
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of participant safety or study results.

• New diagnosis of de novo ALL, lymphomas (T or B cell), or mixed-phenotype acute leukemia.
• Planned 3-4 drug systemic induction chemotherapy with a corticosteroid, vincristine and a single dose or multiple doses of asparaginase, with or without daunorubicin.
• Functioning Central Venous Access Device.
• Must be able to tolerate oral medication or have it administered via an Nasogastric tube (NGT) or GT tube.
• Males and females, age 1 year(365 days) to < 18 (17 years and 364 days) years.

• Subjects scheduled to have > 3 Lumbar Punctures over the course of the study treatment period.
• Prior history of documented DVT or PE in the past 3 months.
• Known inherited bleeding disorder or coagulopathy.
• Major surgery [excluding Central Venous Access Device (CVAD) replacement and bone marrow aspiration and non-open biopsy] within the last 7 days prior to enrollment that may be associated with a risk of bleeding. Open biopsy is considered a major surgery.
• Uncontrolled severe hypertension at enrollment. Severe hypertension is defined as a systolic or diastolic blood pressure (BP) > 5 mm Hg above the 95th percentile as defined by the National High Blood Pressure Education Program Working Group (NHBPEP) established guidelines for the definition of normal and elevated blood pressure in children.
• Extreme hyperleukocytosis, white blood cell (WBC) counts over 200 x 10^9/L (200,000/microL) at the time of enrollment.
• Liver dysfunction manifested by SGTP (ALT) > 5 X Upper limit of normal (ULN) and/or Aspartate aminotransferase (AST) >5 X ULN and/or direct (conjugated) bilirubin > 2 X ULN.
• Renal function < 30% of normal for age and size as determined by the Schwartz formula
• International normalized ratio (INR) > 1.4 and activated partial thromboplastin time (aPTT) > 3 seconds above the upper limit of normal for age, within 1 week prior to enrollment.
• History of allergy to apixaban or Factor Xa inhibitors.
• History of significant adverse reaction or major bleeding related adverse reaction to other anticoagulant or antiplatelet agents.
• History of any significant drug allergy (such as anaphylaxis or hepatotoxicity
• Any investigational drug being administered during the study.

• Must either be currently receiving treatment with, or have a history of having failed to respond to, or have a medical contraindication to at least 1 of the following therapies: oral or intravenous corticosteroids, 6-mercaptopurine, methotrexate or azathioprine OR must either have or have had a history of corticosteroid dependency (that is an inability to successfully taper corticosteroids without a return of the symptoms of ulcerative colitis [UC]) OR required more than 3 courses of corticosteroids in the past year.
• Moderately to severely active UC (as defined by baseline Mayo score of 6 through 12 [endoscopy {sigmoidoscopy or colonoscopy} sub score assigned by local endoscopist], inclusive), including a (sigmoidoscopy or colonoscopy) sub score greater than or equal to (≥ 2).
• If receiving enteral nutrition, must have been on a stable regimen for at least 2 weeks prior to the first administration of study intervention at Week 0. Participants who receive parenteral nutrition are not permitted to enroll in the trial.
• No history of latent or active tuberculosis prior to screening.
• Acceptable evidence of immunity to measles, mumps, rubella, and varicella.

• History of liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric (including suicidality), or metabolic disturbances.
• History of malignancy or macrophage activation syndrome or hemophagocytic lymphohistiocytosis.
• Have UC limited to the rectum only or to < 20 percent (%) of the colon.
• Presence of a stoma.
• Presence or history of a fistula.
• Contraindications to the use of golimumab or infliximab or anti-tumor necrosis factor (TNF-alpha) therapy per local prescribing information.

• At least 18 years of age.
• Evidence of a response (partial response or better based on investigator's determination of response by International Myeloma Working Group [IMWG] criteria) to daratumumab-containing therapy with response duration of at least 4 months.
• Participants must have progressed from or be refractory to their last line of treatment. Relapsed or refractory disease as defined as:
  • Relapsed disease is defined as an initial response to previous treatment, followed by confirmed progressive disease (PD) by IMWG criteria greater than (>) 60 days after cessation of treatment;
  • Refractory disease is defined as less than (<) 25 percent (%) reduction in M-protein or confirmed PD by IMWG criteria during previous treatment or > 60 days after cessation of treatment.
• Received 1 to 3 prior line(s) of treatment of which one contained daratumumab, and completed daratumumab at least 3 months prior to randomization. A single line of therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no more than the equivalent of dexamethasone 40 milligram per day [mg/day] for 4 days) would not be considered prior lines of therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2.
• Women of childbearing potential must have a negative urine or serum pregnancy test at screening within 14 days prior to randomization.

• Previous treatment with daratumumab within the last 3 months prior to randomization.
• Discontinuation of daratumumab due to a daratumumab-related adverse event (AE).
• History of malignancy (other than multiple myeloma) unless all treatment of that malignancy was completed at least 2 years before consent and the patient has no evidence of disease. Further exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years.
• Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase, monoclonal antibodies (mAbs), human proteins, or their excipients, or known sensitivity to mammalian-derived products. Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib).
• Participant is:
  • Known to be seropositive for human immunodeficiency virus (HIV) with one or more of the following: not receiving highly active antiretroviral therapy (ART), had a change in ART within 6 months of the start of screening, receiving ART that may interfere with study treatment, cluster of differentiation (CD)4 count < 350 (unit: cells per cubic millimeter of blood) at screening, acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within 6 months of start of screening, and not agreeing to start ART and be on ART > 4 weeks plus having HIV viral load <400 copies/milliliters (mL) at end of 4-week period (to ensure ART is tolerated and HIV controlled;
  • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (example: participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded;
  • Known to be seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

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

• Men who are currently receiving androgen deprivation therapy (ADT) for the treatment of prostate cancer. ADT is defined by a history of orchiectomy, or ongoing usage of gonadotropin-releasing hormone agonists or antagonists.
• Men receiving next generation androgen axis inhibitor therapies including abiraterone, enzalutamide, apalutamide, and darolutamide are eligible.
• Patients must be on a stable dose of all hormone-directed therapies for at least 28 days prior to registration and must not be planning to discontinue this therapy for at least 42 days following registration.
• Patients receiving radiation therapy during the study period are eligible.
• Eligible patient must have bothersome hot flashes for ≥ 14 days prior to registration, defined by an occurrence of ≥ 28 times per week and of sufficient severity to cause the patient to seek therapeutic intervention.
• Life expectancy of greater than 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status
  •0, 1, or 2.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English.

• No current use or future planned use of any of the following agents during the study period: drugs that are not Food and Drug Administration (FDA) approved for use in humans, androgens, estrogens, progesterone analogs, gabapentin, selective serotonin reuptake inhibitor (SSRI)/serotonin and norepinephrine reuptake inhibitor (SNRI) anti-depressants, cholinergic agonists, cholinesterase inhibitors, or complementary/alternative medicine taken for the purpose of managing hot flashes. Prior use of these agents is permitted as long as they are discontinued before registration.
• No current or prior use of oxybutynin.
• Patients with a history of any of the following contraindications to oxybutynin are not eligible:
  • gastroparesis or gastrointestinal obstructive disorders;
  • significant gastric reflux symptoms not controlled by medication; ulcerative colitis;
  • narrow-angle glaucoma;
  • urinary retention requiring indwelling or intermittent self-catheterization within the prior 6 months;
  • hypersensitivity to oxybutynin or any other components of the product; current uncontrolled hyperthyroidism;
  • uncontrolled coronary artery disease or a history of myocardial infarction within the prior 12 months;
  • New York Heart Association (NYHA) class II-IV congestive heart failure;
  • symptomatic cardiac arrhythmias;
  • current uncontrolled hypertension;
  • myasthenia gravis; or
  • dementia.

Eligibility last updated 11/22/21. Questions regarding updates should be directed to the study team contact.

• History of drug-resistant mesial temporal lobe epilepsy (MTLE)
• If the subject has a vagus nerve stimulator (VNS), must have failed to achieve sustained seizure freedom with the VNS implanted for at least 6 months
• On stable antiepileptic drugs (AEDs) (and/or stable VNS setting, if applicable) and compliant with medication use
• An average of at least 1 complex partial or secondarily generalized seizure compatible with MTLE per month
• Seizure symptoms and/or auras compatible with MTLE
• Video EEG shows evidence of seizures from one temporal lobe consistent with MTLE
• MRI has evidence consistent with mesial temporal lobe sclerosis
• Willing and able to remain on stable AEDs (and stable VNS setting, if applicable) for 12 months following the Visualase procedure
• Willing and able to comply with protocol requirements

• Unwilling or unable to sign the study informed consent form
• Pregnant or intends to become pregnant during the course of the study
• Currently implanted with a device contraindicating MRI
• Progressive brain lesions and/or tumors not associated with epileptic disease state
• History of previous intracranial surgery for treatment of epileptic seizures
• Persistent extra-temporal or predominant contralateral focal interictal spikes or slowing, or generalized interictal spikes on EEG
• Seizures with contralateral or extra-temporal ictal onset on EEG
• Aura and/or ictal behavior suggest an extra-temporal focus
• MRI evidence of epileptogenic, extra-temporal lesions or bilateral hippocampal damage
• If additional testing has been performed, results are discordant with the seizure focus scheduled for ablation
• Non-compliance with AED requirements
• IQ < 70
• Dementia or other progressive neurological disease
• Unstable major psychiatric illness, psychogenic non-epileptic seizures, or medical illness that would contraindicate the Visualase procedure or affect the neuropsychological assessments
• Participation in other research that may potentially interfere with SLATE endpoint(s)
• Allergy to gadolinium

• Written informed consent.
• Male or female at least 18 years old at Screening.
• Initial diagnosis of TED ≥ 2 years but < 10 years prior to Screening. Clinical diagnosis of stable, chronic (inactive) TED, as determined by patient medical records indicating a Clinical Activity Score (CAS) ≤ 1 in both eyes for at least 1 year prior to Screening or all of the following:
  • no progression in proptosis for at least 1 year prior to Screening;
  • if patient has history of diplopia due to TED, no progression in diplopia for at least 1 year prior to Screening;
  • no new inflammatory TED symptoms for at least 1 year prior to Screening.
• CAS ≤ 1 at the Screening and Baseline Visits.
• Proptosis ≥ 3-mm increase from the patient’s baseline (prior to diagnosis of TED), as estimated by treating physician and/or proptosis ≥ 3 mm above normal for race and gender.
• Patients must be euthyroid with the patient’s baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels < 50% above or below the normal limits) at Screening. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the full duration of the trial.
• Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the trial.
• Diabetic patients must have HbA1c ≤ 8.0% at Screening.
• Patients with a history of inflammatory bowel disease, ulcerative colitis or Crohn’s disease must be in clinical remission for at least 3 months, with no history of bowel surgery within 6 months prior to screening and no planned surgery during the trial. Concomitant stable therapies for inflammatory bowel disease without modifications in the 3 months prior to Screening are allowed.
• Women of childbearing potential (including those with an onset of menopause < 2 years prior to Screening, non-therapy-induced amenorrhea for < 12 months prior to Screening, or not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum pregnancy test at Screening and negative urine pregnancy tests at all protocol-specified time points (i.e., prior to each dose and throughout patient’s participation); patients who are sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of contraception during the trial, 1 of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started at least 1 full cycle prior to Baseline and continue for 180 days after the last dose of trial drug. Highly effective contraceptive methods (failure rate < 1% per year), when used consistently and correctly, include implants, injectables, combination oral contraceptives, some intrauterine devices, sexual abstinence and vasectomized partner.
• Male patients, if sexually active with a female partner of childbearing potential, must be surgically sterile or must agree to use a barrier contraceptive method from Screening through 180 days after the last dose of trial drug.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

• Decreased best-corrected visual acuity due to optic neuropathy, defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect or color defect secondary to optic nerve involvement within the last 6 months.
• Corneal decompensation unresponsive to medical management in the study eye.
• Decrease in proptosis of ≥ 2 mm in the study eye between Screening and Baseline.
• Prior orbital irradiation, orbital decompression or strabismus surgery.
• Prior strabismus surgery.
• Alanine aminotransferase or aspartate aminotransferase > 3 × the upper limit of normal or estimated glomerular filtration rate ≤ 30 mL/min/1.73 m^2 at Screening.
• Use of any steroid (intravenous, oral, steroid eye drops) for the treatment of TED or other conditions within 3 weeks prior to Screening. Steroids cannot be initiated during the trial. Exceptions include topical and inhaled steroids and steroids used to treat infusion reactions.
• Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of trial drug or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of trial drug. Use of any other non-steroid immunosuppressive agent within 3 months prior to the first infusion of trial drug.
• Any previous treatment with TEPEZZA, including previous enrollment in this trial or participation in a prior teprotumumab trial.
• Treatment with any monoclonal antibody within 3 months prior to Screening.
• Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results.
• Use of an investigational agent for any condition within 60 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.
• Malignant condition in the past 12 months (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
• Pregnant or lactating women.
• Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the patient.
• Known hypersensitivity to any of the components of TEPEZZA or prior hypersensitivity reactions to monoclonal antibodies.

Eligibility last updated 4/20/22. Questions regarding updates should be directed to the study team contact.

1. Hypertension, defined as a mean supine blood pressure greater than 140/90 mmHg and taking at least one (1) standard of care therapies (including a diuretic, angiotensin converting enzyme inhibitor or angiotensin receptor blocker and a calcium channel blocker)
2. MDRD estimated GFR > 30 mL/min to be calculated at the screening visit by available serum creatinine
3. Male or female African Americans
4. Between the ages of 20 and 70 years
5. Have a body mass index (BMI) within the range of 18–40 kg/m2
6. Be able to communicate effectively with the study personnel
7. Be adequately informed of the nature and risks of the study and give written informed consent prior to receiving study medication

1. Known hypersensitivity or allergy to MANP or other natriuretic peptides
2. Women of child bearing age
3. Having received any investigational drug or device within 30 days prior to entry into the study; 4) A history (within the last 2 years) of alcohol abuse, illicit drug use, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction
4. A history of difficulty with donating blood or donated blood or blood products within 45 days prior to enrollment
5. Clinically significant new illness in the 1 month before screening in the opinion of the investigator
6. History of severe allergies
7. History of coronary artery disease, cerebrovascular disease, or syncope
8. History of epilepsy or other seizure disorder
9. History of organ transplantation
10. Malignancy within 5 years
11. Clinically significant intrinsic renal disease, renal artery stenosis, or history of fibromuscular dysplasia of the renal arteries and
12. Consumption of a phosphodiesterase-5 inhibitor