Prescreening Criteria:

- Diagnosed with NASH on prior liver biopsy

- Type 2 diabetes with high waist circumference or obesity or hepatic steatosis on
ultrasound

- At least 3 of the components of metabolic syndrome

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

Eligibility last updated 11/22/23. Questions regarding updates should be directed to the study team contact.

• Biopsy proven cutaneous mastocytosis with or without evidence of systemic disease.
• Male and female patients, 18 to 80 years of age.
• No UVB treatment of the skin for 6 months prior to study entry.
• No use of topical or systemic corticosteroids for 1 month prior to study entry.
• Good general health as confirmed by medical history.
• Female patients of child-bearing potential with negative urine pregnancy test who agree to use effective methods of birth control or remain abstinent during treatment. Participants must use birth control for the entire study and for at least 1 week after the last application of the study formulation. Acceptable methods of birth control include ongoing hormonal contraception methods, (such as birth control pills, patches, injections, vaginal ring, or implants), barrier methods (such as a condom (for men) or diaphragm used with a spermicide), intrauterine devices, tubal ligation, or abstinence.
• Patients who are willing and capable of cooperating to the extent and degree required by the protocol.
• Patients who read and sign an approved informed consent for this study.

• Vulnerable study population.
• Exposure to ultraviolet B (UVB) radiation to any region of the skin surface for 6 months.
• Regular use of skin lightening agents within 1 month of study entry, including:
  • Topical corticosteroids;
  • Topical bleaching products;
  • Topical retinoids.
• Use of systemic preparations within 1 month of study entry, including:
  • Systemic corticosteroids;
  • Systemic cyclosporine, interferon;
  • Systemic acitretin, etretinate, isoretinoin;
  • Systemic methotrexate;
  • Systemic photoallergic, phototoxic and/or photosensitizing drugs.
• UV light therapy and sunbathing.
• Inability to communicate or cooperate with the Principal Investigator and/or Investigators due to language problems, poor mental development or impaired cerebral function.
• Pregnant or nursing women.
• Women planning a pregnancy within the study period.

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

Eligibility last updated 2/9/23. Questions regarding updates should be directed to the study team contact.

• Adult patients (age ≥ 18 years old).
• Undergoing evaluation for autologous or allogeneic bone marrow transplant (HCT) at Mayo Clinic Rochester.
• Scheduled for pre-HCT pulmonary function test by the primary team.

• Limited mobility requiring use of gait aid or wheelchair.
• Fall risk.

• Subjects with new-onset or relapsing/refractory GCA. 
• Westergren erythrocyte sedimentation rate > 30 mm/hour or c-reactive protein ≥ 1 mg/ dL. 
• Remission of GCA at or before Day 0. 
• Female subjects must be postmenopausal or permanently sterile following documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or tubal ligation or having a male partner with vasectomy as affirmed by the subject, or nonpregnant, nonlactating, and, if sexually active, having agreed to use a highly effective method of contraception. 
• Male subjects must have documented vasectomy or if sexually active must agree to use a highly effective method of contraception with their partners of childbearing potential.

• Transplanted organs (except corneal transplant performed more than 3 months prior to randomization). 
• Concurrent enrollment in another interventional clinical study. 
• Treatment with non-biologic investigational drug therapy within 4 weeks or 5 half-lives of the study agent, whichever was longer, prior to screening. 
• Cell-depleting biological therapies within 12 months prior to Day 0, or noncell-depleting biological therapies within 8 weeks (or 5 half-lives, whichever is longer) prior to screening.
• Treatment with alkylating agents within 12 weeks prior to screening. 
• Intramuscular, Intra-articular or IV corticosteroids within 4 weeks prior to screening.
• Receipt of live (attenuated) vaccine within the 4 weeks before Day 0. 
• Treatment with hydroxychloroquine, cyclosporine A, azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) within 4 weeks of screening. 
• Female subjects who are pregnant, intending to become pregnant, or are breastfeeding. 
• Known history of allergy or reaction to any component of the mavrilimumab or placebo formulation or to any other biologic therapy or prednisone or any of its excipients. 
• Positive (or 2 indeterminate) QuantiFERON test results. 
• Clinically significant active infection or infection requiring hospitalization or IV antibiotics within 12 weeks before screening or opportunistic infection within 6 months before screening. 
• Chronic active hepatitis B infection. 
• Subjects at a high risk of infection, a history of an infected joint prosthesis still in situ, leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections. 
• History of cancer within the last 10 years, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. 
• Evidence of clinically-uncontrolled respiratory disease. 
• History of chronic respiratory tract infections.

• Has participated in and completed the ADMIRE-CD II (NCT03279081) study (i.e., did not discontinue).

• Has been more than 3 months since the participant completed the ADMIRE-CD II study.

Eligibilty Criteria:

• Histologically confirmed cutaneous or visceral angiosarcoma, where curative treatment is either not possible or curative modality therapy is declined by the subject.
  • Note: Radiation induced angiosarcomas are permitted.
• All local diagnostic slides AND 5 x 4-6 micron unstained slides from diagnostic tumor tissue should be available for retrospective central pathology review.
• Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Per RECIST v1.1, clinical lesions will only be considered measurable when they are superficial and P10 mm diameter as assessed using calipers or ruler (e.g., skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is required. When lesions can be evaluated by both clinical exam and imagining, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study. The same method of measurement should be used throughout the study, preferably performed by the same investigator. Areas previously radiated must have demonstrated disease progression at some point over the past 6 months and growth must be subsequent to the last line of anti-cancer directed therapy (e.g., chemotherapy, radiation therapy, surgery).
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown.
  • Therefore, for women of childbearing potential only, a negative pregnancy test done  ≤ 3 days prior to registration is required.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Patient must have completed all prior treatments (including investigational) ≥ 28 days prior to cycle 1 day 1.
  • Exception: prostate patients who are allowed to concurrently receive androgen suppression therapy.
  • Exception: Targeted small molecule chemotherapy or radiation must be completed ≥ 14 days of day 1 of study treatment. For targeted chemotherapies, prior therapies must be completed prior to registration and final dose must have occurred > 5 half-lives prior to cycle 1 day 1.
  • There is no limit to overall number of prior lines of therapy.
• No prior PD-1 inhibitor or PD-L1 inhibitor therapy is permitted.
• No prior administration of VEGF TKI therapy is permitted.
• Recovery to baseline or ≤ grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy, with the exception of fatigue (which should be ≤ grade 2) or alopecia.
• Taxane Naive Patients Only: No prior exposure to taxane therapy of any duration for angiosarcoma.
• Taxane Pre-treated Patients Only: Prior taxane therapy is allowed at any point prior to registration as long as it is ≥ 28 days prior to cycle 1 day 1.
• No major surgery (except the diagnostic biopsy) ≤ 28 days of study registration. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Lasik eye surgery are not considered major surgery. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL.
• Calculated (Calc.) creatinine clearance ≥ 30 mL/min (per Cockcroft-Gault).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
• For patients with documented/suspected Gilbert's disease, bilirubin ≤ 3 x ULN.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN).
• For patients with significant hepatic metastases, ALT and AST ≤ 5 x ULN. No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to liver dysfunction.
• Urine protein:creatinine (UPC) ratio < 1 or urine protein ≤ 1+.
• No uncontrolled central nervous system (CNS) metastases. Patients with history of CNS metastasis will be allowed as long as the metastatic sites were adequately treated as demonstrated by clinical and radiographic improvement, and the patient has recovered from the intervention (no residual adverse events > CTCAE grade 1), and the patient has remained without recurrence of new or worsening CNS symptoms for a period of 28 days prior to registration. Treated CNS metastasis (mets) should have no ongoing requirement for steroids, and no evidence of hemorrhage after treatment for at least 28 days prior to registration.
• No uncontrolled intercurrent illness that would put the patient at undue risk by participation in the study, in the opinion of the investigator.
• No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New York Heart Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months.
• No thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization. Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, and treated with low molecular weight heparin (LMWH) for at least 2 weeks before first dose. Iatrogenic arterial embolization procedures such as tumor arterial embolization or splenic artery embolization are allowed.
• Patients with a requirement for steroid treatment or other immunosuppressive treatment: Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) -Active autoimmune disease requiring systemic treatment (i.e. disease modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. These include but are not limited to patients with a history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease.
  • Note: Patients are permitted to enroll if they have vitiligo; type I diabetes mellitus; hypothyroidism, pituitary or adrenal insufficiency requiring only hormone replacement; psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• No planned palliative procedures for alleviation of pain such as radiation therapy or surgery.
• No untreated or impending spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression.
• No known or suspected contraindications or hypersensitivity to paclitaxel, cabozantinib or nivolumab or to any of the excipients.
• Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization.
  • Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization.
• No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization.
• No lesions invading major pulmonary blood vessels.
• No other clinically significant disorders: serious non-healing wound or ulcer; malabsorption syndrome; uncompensated/symptomatic hypothyroidism; requirements for hemodialysis or peritoneal dialysis; history of solid organ transplantation.
• Chronic concomitant treatment with strong inhibitors and inducers of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors and inducers must discontinue the drug 7 days and 14 days, respectively prior to registration on the study.
• Taxane Naive Patients Only:
  • No clinically significant neuropathy (grade ≥ 2 per NCI CTCAE v5.0).
• Taxane Pre-treated only:
  • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis of DVT within 6 months are allowed if stable and treated with LMWH for at least 2 weeks before first dose.
  • No history of clinically significant coagulopathy. The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test ≤ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment.
  • No uncontrolled hypertension, defined as systolic blood pressure of > 140 mmHg or diastolic pressure > 90 mmHg on anti-hypertensive medications.
  • No known or suspected gastrointestinal disorder affecting absorption of oral medications (for patients getting cabozantinib).
• No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of registration. No concurrent use of parenteral (IV) antibiotics is permitted. Oral antibiotics administered for a defined course with expectation of resolution of infection are permitted at the discretion of the investigator.
• No use of ongoing systemic steroid therapy within 7 days prior to study registration. Dose equivalence of prednisone 10mg daily or less is permitted.
• Taxane Pre-treated only:
  • No current use of aspirin (> 81 mg/day), or any other antiplatelet agents.
  • Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin inhibitors, and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel) is not permitted. Low-dose (prophylactic) low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects with no known brain metastases, no clinically significant hemorrhage, or no complications from a thromboembolic event on the anticoagulation regimen, and who have been on a stable dose of LMWH for at least 2 weeks before first dose.
• Patients must be able to speak and comprehend English or Spanish in order to complete the mandatory patient-completed measures.

Re-Registration Eligibility Criteria (upon progression on Arm 2 only):

• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown.
  • Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 3 days prior to re-registration is required.
• ECOG performance status 0-1.
• Patient must have completed all prior treatments (including investigational Arm 2 paclitaxel) ≥ 28 days prior to cycle 1 day 1.
  • Exception: prostate patients who are allowed to concurrently receive androgen suppression therapy.
  • Note: Re-registration is only permitted after progression on Arm 2.
• No prior PD-1 inhibitor or PD-L1 inhibitor therapy is permitted.
• Recovery to baseline or ≤ grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy, with the exception of fatigue (which should be ≤ grade 2) or alopecia.
• No major surgery (except the diagnostic biopsy) ≤ 28 days of study re-registration. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Lasik eye surgery are not considered major surgery. Subjects with clinically relevant ongoing complications from prior surgery are not eligible .
• Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
• Platelet count ≥ 100,000/mm^3.
• Hemoglobin ≥ 9.0 g/dL.
• Calc. creatinine clearance ≥ 30 mL/min (per Cockcroft-Gault).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
• For patients with documented/suspected Gilbert's disease, bilirubin ≤ 3 x ULN.
• AST/ALT ≤ 2.5 x upper limit of normal (ULN).
• For patients with significant hepatic metastases, ALT and AST ≤ 5 x ULN. No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to liver dysfunction.
• UPC ratio < 1 or urine protein ≤ 1+.
• No uncontrolled CNS metastases. Patients with history of CNS metastasis will be allowed as long as the metastatic sites were adequately treated as demonstrated by clinical and radiographic improvement, and the patients has recovered from the intervention (no residual adverse events > CTCAE grade 1), and the patient has remained without recurrence of new or worsening CNS symptoms for a period of 28 days prior to registration. Treated CNS mets should have no ongoing requirement for steroids, and no evidence of hemorrhage after treatment for at least 28 days prior to registration.
• No uncontrolled intercurrent illness that would put the patient at undue risk by participation in the study, in the opinion of the investigator. 
• No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New York Heart Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months.
• No thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with LMWH for at least 2 weeks before first dose. Iatrogenic arterial embolization procedures such as tumor arterial embolization or splenic artery embolization are allowed.
• Patients with a requirement for steroid treatment or other immunosuppressive treatment: Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayedtype hypersensitivity reaction caused by contact allergen) is permitted.
•  Active autoimmune disease requiring systemic treatment (i.e. disease modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. These include but are not limited to patients with a history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease.
  • Note: Patients are permitted to enroll if they have vitiligo; type I diabetes mellitus; hypothyroidism, pituitary or adrenal insufficiency requiring only hormone replacement; psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event).
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• No planned palliative procedures for alleviation of pain such as radiation therapy or surgery.
• No untreated or impending spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression.
• No known or suspected contraindications or hypersensitivity to cabozantinib or nivolumab or to any of the excipients.
• Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before initiation of therapy.
  • Note: Complete healing of an intra-abdominal abscess must be confirmed before initiation of therapy.
• No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization.
• No lesions invading major pulmonary blood vessels. 
• No other clinically significant disorders: serious non-healing wound or ulcer; malabsorption syndrome; uncompensated/symptomatic hypothyroidism; requirements for hemodialysis or peritoneal dialysis; history of solid organ transplantation.
• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis of DVT within 6 months are allowed if stable and treated with LMWH for at least 2 weeks before first dose.
• No history of clinically significant coagulopathy. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≤ 1.3x the laboratory ULN within 7 days before the first dose of study treatment.
• No uncontrolled hypertension, defined as systolic blood pressure of > 160 mmHg or diastolic pressure > 100 mmHg on anti-hypertensive medications.
• No known or suspected gastrointestinal disorder affecting absorption of oral medications (for patients getting cabozantinib).

• Males or females, aged ≥ 50 years and ≤ 89 years.
• An ETDRS BCVA letter score between ≤ 78 and ≥ 40 in the study eye at Screening Visit 1.
• If both eyes are eligible, the study eye must be the participant’s worse-seeing eye, as determined by the investigator prior to randomization.
• Must have a diagnosis of subfoveal CNV secondary to AMD in the study eye, along with fluid within the parafovea (3-mm center of the macula, based on the early treatment diabetic retinopathy grid) at Screening Visit 1.
  • CNV lesion characteristics as assessed by the CRC: lesion size needs to be less than 10-disc areas (typical disc area = 2.54 mm^2).
• Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye.
• Must be willing and able to comply with all study procedures and be available for the duration of the study.
• Women must be postmenopausal (defined as being at least 12 consecutive months without menses) or surgically sterilized (ie, having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral oophorectomy).
• Male participants engaged in a sexual relationship with a woman of childbearing potential must be willing to use condoms (and their partners to use a medically accepted method of contraception) from the day of RGX-314 administration until 4 weeks after RGX-314 administration.
• Must be willing and able to provide written, signed informed consent.
• Response criteria: Based on the Screening Visit 2 SD-OCT, participants must have improvement in fluid of > 50 μm or, if the participant has < 50 μm of fluid, then any improvement in fluid and have a CRT < 400 μm at the screening visit, as determined by the CRC. Note that, if the participant has disease other than fluid contributing to an increase (i.e., pigment epithelial detachment [PED] or subretinal hyper-reflective material [SHRM]) in CRT, they will be enrolled if they have < 50 μm of fluid (intraretinal or subretinal), as determined by the CRC.
• Additionally, participants who received 10 to 12 anti-VEGF injections in the study eye in the 12 months prior to Screening Visit 1 must demonstrate a complete fluid response as determined by CRC review of the Screening Visit 2 SD-OCT, defined as complete resolution of fluid.

• CNV or macular edema in the study eye secondary to any causes other than AMD.
• Subfoveal fibrosis or atrophy as determined by the CRC.
• Study eye that required > 12 anti-VEGF injections in the 12 months prior to the Screening Visit
• Any condition in the investigator’s opinion that could limit VA improvement in the study eye.
• Active or history of retinal detachment in the study eye.
• Advanced glaucoma in the study eye defined as IOP of > 23 mmHg not controlled by 2 IOP-lowering medications or any invasive procedure to treat glaucoma (e.g., shunt, tube, or minimally invasive glaucoma surgery [MIGS] devices; selective laser trabeculectomy, and argon laser trabeculoplasty are permitted).
• Study eye with nAMD diagnosed > 4 years from Screening Visit 1.
• Any condition in the study eye that, in the opinion of the investigator, may increase the risk to the participant, require either medical or surgical intervention during the course of the study to prevent or treat vision loss, or interfere with study procedures or assessments.
• History of intraocular surgery in the study eye within 12 weeks prior to Screening Visit 1. Yttrium aluminum garnet capsulotomy is permitted if performed > 10 weeks prior to the Screening Visit 1.
• History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to Screening Visit 1.
• Presence of any implant in the study eye at Screening Visit 1 (excluding intraocular lens or MIGS).
• History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation in the 5 years prior to Screening Visit 1. Localized basal cell carcinoma will be permitted.
• Receipt of any investigational product within the 30 days of enrollment or 5 half-lives of the investigational product, whichever is longer.
• Received gene therapy.
• History of retinal toxicity caused by a therapy that may affect VA, eg, chloroquine or hydroxychloroquine.
• Ocular or periocular infection in the study eye that may interfere with the surgical procedure.
• Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months.
• Uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
• Any participant with the following laboratory values at Screening Visit 1 will be withdrawn from study:
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN);
  • Total bilirubin > 1.5 × ULN, unless the participant has a previously known history of Gilbert’s syndrome and a fractionated bilirubin that shows conjugated bilirubin < 35% of total bilirubin;
  • Prothrombin time > 1.5 × ULN, unless the participant is anticoagulated:
    • Participants who are anticoagulated will be monitored by local labs and managed per local practice to hold or bridge anticoagulant therapy for the study procedure; consultation with the Medical Monitor is also required;
  • Hemoglobin < 10 g/dL for male participants and < 9 g/dL for female participants;
  • Platelets < 100 × 10^3/μL;
  • Estimated glomerular filtration rate < 30 mL/min/1.73 m^2.
• Currently taking anticoagulation therapy for which holding anticoagulation therapy for RGX-314 administration is not indicated or considered to be unsafe in the opinion of the treating investigator (i.e., retinal surgeon), as well as the physician prescribing anticoagulation for the participant.
• Any concomitant treatment that, in the opinion of the investigator, may interfere with ocular surgical procedure or healing process.
• Known hypersensitivity to ranibizumab or any of its components.
• Has a serious, chronic, or unstable medical or psychological condition that, in the opinion of the investigator or Sponsor, may compromise the participant’s safety or ability to complete all assessments and follow-up in the study.
• Prior corneal transplant in the study eye.
• Pigmentary glaucoma in the study eye.

Inclusion Criteria for Participants in the Control Arm Who Cross Over to RGX-314 Treatment After Week 54:

• Study eye will be the eye that qualified at randomization.
• Study eye has a CRT < 400 μm of fluid or (in cases where a participant may have nonfluid elevation in the CRT, eg, pigment epithelial defect) < 50 μm of excess fluid, as confirmed by the masked CRC.
• Male participants engaged in a sexual relationship with a woman of childbearing potential must be willing to use condoms (and their partners to use a medically accepted method of contraception) from the day of RGX-314 administration until 4 weeks after RGX-314 administration.

• CNV or macular edema in the study eye secondary to any causes other than AMD.
• New subfoveal fibrosis or atrophy since randomization, as determined by the CRC, or any condition preventing VA improvement in the study eye.
• Ocular or periocular infection in the study eye that may interfere with the surgical procedure.
• Myocardial infarction, cerebrovascular accident, or transient ischemic attacks since randomization.
• Uncontrolled hypertension (systolic BP > 180 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
• Any concomitant treatment that, in the opinion of the investigator, may interfere with ocular surgical procedure or healing process.
• History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation since randomization. Localized basal cell carcinoma will be permitted.
• Currently taking anticoagulation therapy for which holding anticoagulation therapy for RGX-314 administration is not indicated or considered to be unsafe in the opinion of the treating investigator as well as the physician prescribing anticoagulation for the participant.

Eligibility last updated 10/27/21. Questions regarding updates should be directed to the study team contact.

• Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable).
• Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
• Males or females, age ≥ 18 years.
• ECOG Performance Status/WHO Performance Status ≤ 1.
• Life expectancy of > 24 months.
• Absolute neutrophil count > 1.5 x 10^9/L.
• Hemoglobin > 9.0 g/dL.
• Platelets > 100 x 10^9/L.
• Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl).
• ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
• Serum creatinine < 1.5 x ULN .
• LDH serum level ≤ 1.5 x ULN.
• Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV negative serum HBV-DNA is also required.
• All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above.
• All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.  Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients in Arm 1).
• Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e., spermicidal gel plus condom) from the screening to three months following the last study drug administration.
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

• Uveal melanoma or mucosal melanoma
• Evidence of distant metastases at screening.
• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except: cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry.
• Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Inadequately controlled cardiac arrhythmias including atrial fibrillation.
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
• LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
• Uncontrolled hypertension.
• Ischemic peripheral vascular disease (Grade IIb-IV).
• Severe diabetic retinopathy.
• Active autoimmune disease.
• History of organ allograft or stem cell transplantation.
• Recovery from major trauma including surgery within 4 weeks prior to enrollment.
• Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
• Breast feeding female.
• Anti-tumor therapy (except small surgery) within 4 weeks before enrollment.
• Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment.
• Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment.
• Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
• Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
• Previous enrolment and randomization in the same study.

Eligibility last updated to match clinicaltrials.gov 3/8/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Progressive or recurrent WHO Grade IV IDH wildtype glioblastoma (including molecular glioblastoma and gliosarcoma).
• Have an enhancing mass on MRI amenable to resection or biopsy of the tumor (as determined by the neurosurgeon pre-operatively) and histological diagnosis of glioblastoma from a prior biopsy or surgery.
• Willing to undergo resection or biopsy of their glioblastoma at Mayo Clinic in Rochester, MN.
• ECOG Performance Status (PS) of 0 or 1 and KPS ≥ 70.
  • Note: PS must be assessed again within 7 days prior to first dose of study drug.
• The following laboratory values obtained ≤ 15 days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Hemoglobin ≥ 9.0 g/dL without transfusion or EPO dependency (≤ 7 days prior to assessment);
  • Creatinine ≤ 2.0 x ULN OR measured or calculated creatinine clearance (per institutional standard) must be ≥ 45 ml/min;
  • Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ULN for patients with total bilirubin levels > 1.5 x ULN;
  • Aspartate transaminase (AST) AND alanine transaminase (ALT) ≤ 2.5 x ULN;
  • INR/PT/aPTT ≤ 1.5 × ULN OR if patient is receiving anticoagulant therapy then INR or aPTT is within target range of therapy.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only (POCBP).
  • Note: If testing done for eligibility is > 72 hours prior to first dose, then pregnancy testing must be repeated, and result must be negative for patient to receive treatment.
• POCBP or able to father a child must be willing to use adequate contraception starting with first dose through 120 days after last dose. 
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to provide tissue and blood samples for correlative research purposes.

Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown:

• Pregnant persons.
• Nursing persons.
• Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception.
• Signs or symptoms of life-threatening raised intracranial pressure: as defined by the treating neurosurgeon, including severe headache, nausea, decreasing level of consciousness, precluding 4-7 day delay in scheduling neurosurgery.
• Prior treatment.
• Received bevacizumab (AVASTIN) ≤ 28 days prior to registration.
  Note: Bevacizumab is allowed for symptom control during the adjuvant phase of the study.
• Received a live vaccine ≤ 30 days prior to registration.
• Major surgery ≤ 28 days prior to registration.
• Requirement for dexamethasone dose of > 2mg/day ≤ 2 days prior to registration.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
• 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 requiring systemic treatment ≤ 1 year prior to registration.
• History of myocardial infarction ≤6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Active autoimmune disease that has required systemic treatment (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) ≤ 2 years prior to registration.
  • Note: 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.
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Known history of active TB (Bacillus Tuberculosis).
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Hypersensitivity to pembrolizumab or any of its excipients.
• Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

• Age 18 years old and above.
• Diagnosis of prolactinoma.
• Ability to provide informed consent.

• None.

• Confirmed genetic diagnosis of Friedreich’s Ataxia (FA), with onset being before 25 years of age.
• Protocol specified ranges for antibodies.
• Protocol specified measures of FA cardiomyopathy.

• Protocol specified ranges for left ventricular ejection fraction (LVEF) as measured by cardiac ECHO.
• Uncontrolled diabetes.
• Abnormal liver function.
• Active infection of any type, including hepatitis virus (A, B or C) or human immunodeficiency virus (HIV-1 and HIV-2).
• Contraindication to cardiac MRI.
• Contraindications to cardiac biopsies.
• Participants who are receiving systemic corticosteroids or other immunosuppressive medications.
• History of significant coronary artery disease or any structural heart or vascular disease other than FA cardiomyopathy.
• Presence of clinically significant, hemodynamically unstable arrhythmias, requiring physician intervention.
• Presence of clinically significant abnormalities as determined by the investigator, other than ECG abnormalities related to FA.
• Uncontrolled psychiatric disease.

Other Inclusion/Exclusion Criteria to be applied as per protocol.

Eligibility last updated 7/13/23. Questions regarding updates should be directed to the study team contact.

• Evidence of a personally signed and dated informed consent document indicating that the subject or their parent(s)/legal guardian, if applicable, have been informed of all pertinent aspects of the study.
• Male or female subjects of 12 years of age or older, at the time of informed consent and body weight greater than or equal to 40 kg. Adolescent subjects below the age of 18 years old will only be enrolled in this study if instructed by the sponsor and approved by the country or regulatory/health authority. If these approvals have not been granted, only subjects aged 18 years and older will be enrolled.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
• Must have completed the full treatment period of a qualifying Phase 3 study OR must have completed the full rescue treatment period of a qualifying Phase 3 study (if applicable).
• Female subjects who are of childbearing potential (which includes all female subjects aged 12 years and older, regardless of whether they have experienced menarche) must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply:
  • Female subjects of childbearing potential must have a confirmed negative pregnancy test prior to randomization;
  • Female subjects of childbearing potential must agree to use a highly effective method of contraception for the duration of the active treatment period and for at least 28 days after the last dose of investigational product.
• Female subjects of non childbearing potential must meet at least 1 of the following criteria:
  • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
  • Have medically confirmed ovarian failure; or
  • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
• Must agree to avoid prolonged exposure to the sun and not to use tanning booths, sun lamps or other ultraviolet light sources during the study.
• Must agree to avoid use of prohibited medications throughout the duration of the study.

• Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
• Currently have active forms of other inflammatory skin diseases; i.e., not AD or have evidence of skin conditions (eg, psoriasis, seborrheic dermatitis, Lupus) at the time of Day -1 that would interfere with evaluation of atopic dermatitis or response to treatment.
• Discontinued from treatment (or rescue treatment period/open-label run-in period, if applicable) early in a qualifying Parent study OR triggered a discontinuation criterion at any point during the qualifying Parent study which in the opinion of the investigator, or sponsor, is an ongoing safety concern.
• Ongoing adverse event in the qualifying Parent study which in the opinion of the investigator, or sponsor, is an ongoing safety concern.
• Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.

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

• Men or women between 18 and 65 years of age at the time of informed consent (IC).
• Have an EoE diagnosis prior to screening and histologically active disease with an esophageal peak eosinophil count (PEC) of ≥ 15 eosinophils (eos)/high power field (hpf) (~ 60 eos/mm^2 ) from any level (proximal, mid, or distal) of the esophagus at the Screening esophagogastroduodenoscopy (EGD).
• Have dysphagia, defined as solid food going down slowly or getting stuck in the throat with an average frequency of ≥ 2 episodes per week over 2 weeks (as documented using the Dysphagia Symptom Questionnaire (DSQ) during the Screening period).

• History of any of the following non-EoE conditions or procedures that may interfere with the evaluation of or affect the histologic, endoscopic, or symptom endpoints of the study:
  • Conditions that cause or potentially contribute to esophageal eosinophilia (eg, eosinophilic gastritis [EG], gastroenteritis, or colitis with esophageal involvement, severe gastroesophageal reflux disease [GERD], achalasia and other disorders of esophageal dysmotility, hypereosinophilic syndrome, Crohn’s disease [CD] with esophageal involvement, esophageal infection [fungal, viral], connective tissue diseases, hypermobility syndromes, autoimmune disorders and vasculitides, dermatologic conditions with esophageal involvement [ie, pemphigus], drug hypersensitivity reactions, pill esophagitis, graft versus host disease, Mendelian disorders [e.g., Marfan syndrome Type II, hyper-immunoglobulin E (IgE) syndrome, phosphatase and tensin homolog hamartoma tumor syndrome, Netherton syndrome, severe atopy metabolic wasting syndrome]);
  • Conditions that interfere with the evaluation of the esophagus (e.g., esophageal varices with risk of spontaneous bleed, high-grade esophageal stenosis where an 8- to 10-mm endoscope could not pass through the stricture without dilation at the time of Screening EGD);
  • Conditions or procedures that cause or potentially contribute to dysphagia (e.g., Barrett’s esophagus, erosive esophagitis Los Angeles Grade B or above, significant hiatal hernia [≥ 4 cm], esophageal resection, fundoplication, gastric sleeve surgery).
• Undergone dilation of an esophageal stricture within 12 weeks prior to Screening EGD.
• Use of corticosteroids for the treatment of EoE within 8 weeks prior to Screening EGD.
• Discontinue, initiate, or change dosing (dosage/frequency) of the following therapies for EoE within 8 weeks prior to Screening EGD. Subjects on any of the following therapy need to stay on a stable regimen during study participation:
  • Elemental diet;
  • EoE food trigger elimination diet;
  • PPI therapy.
• Used any immunotherapy/desensitization including oral immunotherapy (OIT) or sublingual immunotherapy (SLIT) within 12 months prior to the Screening EGD Note: Stable (i.e., ≥ 6 months prior to the Screening EGD) subcutaneous immunotherapy (SCIT) is permitted. Subjects on SCIT need to stay on a stable treatment during study participation.
• Used any of the following immunomodulatory therapies within the timeframes prior to Baseline as indicated below. The Medical Monitor should be consulted with any questions related to prior use of unlisted immunomodulatory therapies.

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

• Patients with life or limb threatening traumatic injury to an arterial vessel in the limb or torso, other than the heart, which requires replacement or reconstruction.
• Preoperative imaging or clinical examination indicates the damaged vessel has a defect length of ≤ 38cm and is appropriately size matched to the 6mm Human Acellular Vessel (HAV) per the judgment of the treating surgeon taking into account vasoconstriction and situational inflow and outflow considerations.
• Autologous vein graft is either not feasible in the judgment of the treating surgeon (e.g., because of lack of availability of suitable conduit, presence of severe venous insufficiency) or is not desirable because of the urgency of revascularization.
• Aged 18 to 85 years old, inclusive.
• Able to communicate meaningfully with investigative staff, and able to comply with entire study procedures. If the patient is unconscious, then information from a reliable witness indicates that the patient would normally be able to comply with study procedures.
• Patient or relative is able, willing and competent to give informed consent.
• Life expectancy of at least 1 year.

• Mangled Extremity Severity Score (MESS) of ≥ 7.
• Limb at high risk of amputation despite vascular reconstruction (e.g., because of crush injury).
• Catastrophic injuries that make survival unlikely (e.g., Abbreviated Injury Scale (AIS) > 5 or Injury Severity Score (ISS) > 60).
• HAV may not be used for coronary artery repair.
• Known pregnant women.
• Known medical condition which would preclude long term antiplatelet therapy after resolution of acute injuries.
• Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of the HAV.
• Previous exposure to HAV.
• Known participation in any investigational study within the last 30 days.
• Employees of the sponsor or patients who are employees or relatives of the investigator.

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

• Patients must be greater than or equal to 3 years and less than 22 years of age at the time of enrollment.
• Patients must be newly diagnosed and have:
  • Eligibility confirmed by rapid central pathology and molecular screening review on APEC14B1:
    • classical histologic type (non LC/A) WNT medulloblastoma;
    • positive nuclear β-catenin by IHC;
    • positive for CTNNB1 mutation;
    • negative for MYC and MYCN by FISH.
• Patient must have negative lumbar CSF cytology.
  • Note: CSF cytology for staging should be performed no sooner than 14 days post operatively to avoid false positive CSF. Ideally, CSF should be obtained between Day 14 and Day 21 to allow for final staging status before enrollment onto the study. Patients with positive CSF cytology obtained 0 to 14 days after surgery should have cytology repeated to determine eligibility and final CSF status.  Patients with negative CSF cytology from lumbar puncture obtained 0 to 14 days after surgery do not need cytology repeated. Patients with negative CSF cytology from lumbar puncture obtained prior to surgery do not need cytology repeated post-operatively.
• Patients must have eligibility confirmed by Rapid Central Imaging Review on APEC14B1. Patients must have ≤ 1.5 cm2 maximal cross-sectional area of residual tumor (see Section 3.1.4). Whole brain MRI with and without gadolinium and spine MRI with gadolinium must be performed.
• Patients must be enrolled, and protocol therapy must be projected to begin, no later than 36 days after definitive diagnostic surgery (Day 0). 
• Adequate Bone Marrow Function Defined As:
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/μL;
  • Platelet count ≥ 100,000/μL (transfusion independent);
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions).
• Adequate Renal Function Defined As:
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m^2; or
  • A serum creatinine based on age/gender as follows:
    • Age | Maximum Serum Creatinine (mg/dL) | Male | Female
    • 3 to < 6 years | 0.8 | 0.8
    • 6 to < 10 years | 1.0 | 1.0
    • 10 to < 13 years | 1.2 | 1.2
    • 13 to < 16 years | 1.5 | 1.4
    • ≥ 16 years | 1.7 | 1.4
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
• Adequate Liver Function Defined As:
  • Total or direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for age; and
  • SGPT (ALT) ≤ 135 U/L (3x ULN). For the purpose of this study, the ULN for SGPT is 45 U/L.
• Central Nervous System Function Defined As:
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
  • Patients must not be in status epilepticus, a coma or on assisted ventilation at the time of study enrollment.
• Patients must have receptive and expressive language skills in English, French, or Spanish to complete the QoL and Neurocognitive assessments. If a patient meets these criteria but the parent/guardian speaks a language other than English, French, or Spanish, the patient may still be enrolled and tested, and the parent-report measures should be omitted.

• Patients with metastatic disease by either MRI evaluation (brain and spine) or lumbar CSF cytology are not eligible. Patients who are unable to undergo a lumbar puncture for assessment of CSF cytology are ineligible.
• Patients must not have received any prior radiation therapy or chemotherapy (tumor-directed therapy) other than surgical intervention and/or corticosteroids.
• Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.
• Patients with a history of moderate to profound intellectual disability (i.e., IQ < 55) are not eligible for enrollment.
  • PLEASE NOTE: Children with a prior history of attention deficit hyperactivity disorder (ADHD) or a specific learning disability (e.g., dyslexia) are eligible for this study.
• All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• All institutional, FDA, and NCI requirements for human studies must be met.

• Are aged 18 years and over.
• Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), (oral cavity, oropharynx, hypopharynx, or larynx) which has progressed on or after previous systemic cancer therapy and is not amenable to curative therapy
• Received prior treatment using a PD-(L)1 inhibitor.
• Prior platinum failure.
• Received 1 or 2 prior systemic regimens for recurrent or metastatic SCCHN.
• Has measurable disease per RECIST 1.1.
• A fresh or recently acquired tumor tissue for the purpose of biomarker testing.
• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

• Head and neck cancer of any primary anatomic location in the head and neck not specified in the inclusion criteria, including participants with SCCHN of unknown primary or non-squamous histologies.
• Had prior cetuximab therapy (unless it was administered in curative locally advanced setting with radiotherapy and no disease progression for at least 6 months following the last cetuximab dose).
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis.
• Any concurrent anticancer treatment, except for hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy).

• Histologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) with < 10% CD30 expression by immunohistochemistry in the following subtypes (by local review): nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (TFH-PTCL), follicular T-cell lymphoma, PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma.
• Patients will be stratified by presence or absence of TFH phenotype (i.e., diagnosis of AITL, TFH-PTCL, follicular T-cell lymphoma) based on local review of pathology. Determination of TFH phenotype can be defined by expression of two or more of the following markers CD10, BCL6, CXCL13, ICOS, and PD1 by immunohistochemistry.
• Measurable disease as defined by the Lugano criteria.
• No prior systemic therapy for lymphoma (excluding corticosteroids).
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to registration is required.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Platelet count ≥ 75,000/mm^3 (≥ 50,000/mm^3 if secondary to bone marrow involvement from lymphoma per investigator assessment; the first 12 patients on each arm of the study must have platelets ≥ 75,000/mm^3 regardless of bone marrow involvement).
• Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) ≤ 3.0 x upper limit of normal (ULN) * Except in subjects with documented liver involvement by lymphoma.
• Calculated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula.
• Total bilirubin ≤ 2.0 x ULN * Except in cases of Gilbert's Syndrome or documented liver or pancreatic involvement by lymphoma.
• Archival tissue must be available for submission.
• No active viral infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Those who are seropositive (e.g., hepatitis B core antibody [Ab] positive) are permitted if they are negative by polymerase chain reaction (PCR). Those who are seropositive for hepatitis B and are negative for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by PCR must receive concomitant hepatitis B directed antiviral therapy. Those who have hepatitis C Ab positivity who have completed curative therapy for hepatitis C with negative hepatitis C PCR are eligible.
• Patients with history of HIV are eligible if they have an undetectable viral load for at least 6 months.
• No active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment).
• Patients with Epstein-Barr virus (EBV) viremia related to their lymphoma are permitted.
• Patients must have documented left ventricular ejection fraction of ≥ 45%.
• No significant active cardiac disease within the previous 6 months including: 
  • New York Heart Association (NYHA) class III or IV congestive heart failure;
  • Unstable angina or angina requiring surgical or medical intervention; and/or
  • Myocardial infarction.

• Patients with expression of CD30 in ≥ 10% of the tumor (based on local immunohistochemistry review) regardless of histology will not be permitted.
• Patients with a diagnosis of other PTCL subtype histologies other than those specified in the inclusion criteria are excluded including large cell transformation of mycosis fungoides.
• Patients known to have HTLV 1/2.
• Patients with known central nervous system involvement.
• No concurrent malignancy requiring active therapy within the last 3 years with the exception of basal cell carcinoma limited to the skin, squamous cell carcinoma limited to the skin, carcinoma in situ of the cervix, breast or localized prostate cancer. Adjuvant hormonal therapy for cancer previously treated for curative intent is permitted.
• No contraindication to any drug in the chemotherapy regimen, including neuropathy ≥ grade 2.
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

Eligibility last updated 9/30/21. Questions regarding updates should be directed to the study team contact.

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

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

• Male or female.
• 18 to 80 years of age, inclusive.
• Lack of cortisol suppression (> 1.8 μg/dL serum cortisol with adequate dexamethasone levels) on either 1-mg overnight or 2-mg 48-hour DST during Screening.
• Suppressed or low (≤15 pg/mL) early-morning ACTH levels on at least 2 occasions during Screening.
• A radiologically confirmed benign adrenal lesion (single adenoma, multiple adenomas, hyperplasia [≥ 3 times the size of the normal adrenal gland]) within 3 years prior to screening
• Has at least 1 of the following at Baseline:
  • DM (fasting plasma glucose ≥ 126 mg/dL and/or 2-hour oGTT plasma glucose ≥ 200  mg/dL at 2 hours, or HbA1c ≥ 6.5%), or IGT (plasma glucose ≥ 140 mg/dL and < 200 mg/dL on a 2-hour oGTT) (American Diabetes Association 2020);
  • Systolic hypertension (mean SBP ≥ 130 to ≤ 170 mm Hg) based on 24-hour ABPM (Parati et al. 2014).
• If receiving medical treatment for DM/IGT or hypertension,there has been no increase in medication dosage for at least 4 weeks prior to Baseline assessment.
• For women of childbearing potential, has a negative serum pregnancy test at Screening and negative urine pregnancy test at Baseline.

• Has severe, uncontrolled hypertension (mean SBP > 170 mm Hg or mean DBP > 110 mm Hg at Screening), based on 24-hour ABPM.
• Has poorly controlled DM (HbA1c > 12% at Screening).
• Has DM Type 1. 
• Has abnormal liver test results (total bilirubin >1.5 × ULN or elevated alanine aminotransferase or aspartate aminotransferase > 3 × ULN at Baseline).
• Has severe renal insufficiency (glomerular filtration rate ≤ 29 mL/min at Baseline).
• Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
• Has prolonged QT interval corrected for heart rate using Fridericia’s equation (QTcF) (> 450 ms for men and > 470 ms for women) with normal QRS interval (500 ms with wide QRS interval (≥ 120 ms).
• Has persistent atrial fibrillation.
• Has used or plans to use any treatments for Cushing syndrome within 12 weeks prior to Screening and throughout the study, including mifepristone, metyrapone, osilodrostat, ketoconazole, fluconazole, or any investigational drug for treatment of Cushing syndrome.
• Patients who require inhaled glucocorticoids and have no alternative option if their condition deteriorates during the study.
• Has adrenocortical carcinoma.
• Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushing syndrome based on medical history (such as patients with severe obesity, major depression, or a history of alcoholism) should undergo a dexamethasone-CRH/DDAVP stimulation test (Yanovski et al.1993, Giraldi et al. 2007, Yanovski et al. 1998) to rule-in or rule-out this possibility.
• Has a history of cyclic Cushing syndrome with fluctuating clinical manifestations.
• Has autonomous cosecretion of aldosterone.
• Has plans for adrenalectomy or nodulectomy during the study, including follow-up.
• Has taken any non-Cushing syndrome investigational drug within 4 weeks prior to Baseline, or within less than 5 times the drug’s half-life, whichever is longer.
• Ongoing use of antidiabetic, antihypertensive, antidepressant or lipid-lowering medications that are highly dependent on CYP3A for clearance and that cannot undergo dose modification upon coadministration with strong CYP3A inhibitors.
• Ongoing use of any strong CYP3A4 inducer or any other prohibited medications.
• Is pregnant or lactating.
• Is a female patient of childbearing potential who cannot use a highly effective method of contraception (including all women < 50 years old, women whose surgical sterilization was performed < 6 months ago, and women who have had a menstrual period in the last 2 years).
• Has an acute or unstable medical problem that could be aggravated by treatment with the investigational study drug.
• Has a history of severe reaction to the study drug, to a similar class of drug, or to the study drug’s excipient.
• In the Investigator’s opinion, should not participate in the study or may not be capable of following the study schedule.
• Has known HIV, hepatitis B, or hepatitis C infection and is taking medication for treatment of HIV, hepatitis B, or hepatitis C infection.
• Has used mitotane prior to Baseline.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

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

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

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

• Age 18 years or older.
• Dysplastic BE (either low or high grade) or BE-related intramucosal EAC on initial diagnosis successfully treated with endoscopic therapy with negative surveillance endoscopy for at least one year from endoscopic therapy.
• Dysplastic BE (either low or high grade) or BE-related intramucosal EAC on initial diagnosis successfully treated with initial endoscopic therapy with remission across two subsequent surveillance endoscopies but evidence of recurrence of intestinal metaplasia, dysplasia, or EAC by the third surveillance endoscopy.
• Tolerance of endoscopy.
• Ability to give informed consent.

• Age < 18 years old.
• Pregnancy.
• Prior gastric surgery.
• Use of any bile acid sequestrants (cholestyramine, colestipol, and colesevelam) at the time of enrollment.
• Evidence of biliary obstruction or cholestasis due to any reason, defined as total bilirubin above the upper limit of normal, alkaline phosphatase above the upper limit of normal, and/or clinical evidence of jaundice.
• Active esophagitis or stricture precluding passage of endoscope and completion of endoscopic procedure.
• Coagulopathy, defined as INR > 1.5 or platelet level 50,000 precluding completion of endoscopic procedure.

• Female patients ≥ 18 years of age.
• Patients must have a confirmed diagnosis of high-grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.
• Patients must have platinum-resistant disease:
  • Patients who have only had 1 line of platinum based therapy must have received at least 4 cycles of platinum, must have had a response (CR or PR) and then progressed between > 3 months and ≤ 6 months after the date last dose of platinum;
  • Patients who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum.
  • Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.
  • Note: Patients who are platinum-refractory during front-line treatment are excluded (see exclusion criteria).
• Patients must have progressed radiographically on or after their most recent line of therapy.
• Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low risk, medically routine procedure for immunohistochemistry (IHC) confirmation of FRα positivity.
• Patient’s tumor must be positive for FRα expression as defined by the Ventana FOLR1 (FOLR-2.1) CDx assay.
• Patients must have at least one lesion that meets the definition of measurable disease by RECIST v1.1 (radiologically measured by the Investigator).
• Patients must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment:
  • Adjuvant ± neoadjuvant considered one line of therapy
  • Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (i.e., not counted independently);
  • Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (i.e., not counted independently);
  • Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.
• Patient must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
• Time from prior therapy:
  • Systemic antineoplastic therapy (5 half-lives or 4 weeks, whichever is shorter);
  • Focal radiation completed at least 2 weeks prior to first dose of study drug.
• Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities.
• Major surgery must be completed at least 4 weeks prior to first dose and have recovered or stabilized from the side effects of prior surgery
• Patients must have adequate hematologic, liver, and kidney functions defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L (1,500/μL) without G-CSF in the prior 10 days or long-acting WBC growth factors in the prior 20 days;
  • Platelet count ≥ 100 x 10^9 /L (100,000/μL) without platelet transfusion in the prior 10 days;
  • Hemoglobin ≥ 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 21 days;
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN f. Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN);
  • Serum albumin ≥ 2 g/dL.
• Patients or their legally authorized representative must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
• Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) in while on study drug and for at least 3 months after the last dose of MIRV or at least 6 months after the last dose of Pac, PLD, or Topo.
• WCBP must have a negative pregnancy test within 4 days prior to the first dose of study drug.

• Patients with endometrioid, clear cell, mucinous, or sarcomatous histology, mixed tumors containing any of the above histologies, or low-grade or borderline ovarian tumor.
• Patients with primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within 3 months of the last dose of first line platinum-containing chemotherapy.
• Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow.
• Patients with > Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE).
• Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision.
• Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
  • Active hepatitis B or C infection (whether or not on active antiviral therapy);
  • HIV infection;
  • Active cytomegalovirus infection;
  • Any other concurrent infectious disease requiring IV antibiotics within 2 weeks before starting study drug.
  • Note: Testing at screening is not required for the above infections unless clinically indicated.
• Patients with history of multiple sclerosis or other demyelinating disease and/or LambertEaton syndrome (paraneoplastic syndrome).
• Patients with clinically significant cardiac disease including, but not limited to, any one of the following:
  • Myocardial infarction ≤ 6 months prior to first dose;
  • Unstable angina pectoris;
  • Uncontrolled congestive heart failure (New York Heart Association > class II);
  • Uncontrolled ≥ Grade 3 hypertension (per CTCAE);
  • Uncontrolled cardiac arrhythmias.
• Patients assigned to PLD stratum only:
  • Left ventricular ejection fraction (LVEF) below the institutional limit of normal as measured by echocardiography (ECHO) or multigated acquisition (MUGA) scan.
• Patients with a history of hemorrhagic or ischemic stroke within six months prior to randomization.
• Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C).
• Patients with a previous clinical diagnosis of non-infectious interstitial lung disease (ILD), including noninfectious pneumonitis.
• Patients with required use of folate-containing supplements (e.g., folate deficiency).
• Patients with prior hypersensitivity to monoclonal antibodies.
• Women who are pregnant or lactating.
• Patients with prior treatment with MIRV or other FRα-targeting agents.
• Patients with untreated or symptomatic central nervous system (CNS) metastases.
• Patients with a history of other malignancy within 3 years prior to randomization.
  • Note: does not include tumors with a negligible risk for metastasis or death (e.g., adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast).
• Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
• People who are detained through a court or administrative decision, receiving psychiatric care against their will, adults who are the subject of a legal protection order (under tutorship/curatorship), people who are unable to express their consent, and people who are subject to a legal guardianship order.
• Simultaneous participation in another research study, in countries or localities where this is the health authority guidance.

• Women and minorities may be included.
• Measurable stage III, measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial cancer.
• Pathology report showing results of institutional MMR IHC testing.
• Histologic confirmation of the original primary tumor is required (submission of pathology report[s] is required). Patients with the following histologic types are eligible:
  • Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.). 
• Submission of tumor specimens for centralized MMR IHC testing is required after Step 1 and before Step 2 registration.
• In patients with measurable disease (stage III and IVA), lesions will be defined and monitored by RECIST version (v) 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when measured by computed tomography (CT) or magnetic resonance imaging (MRI). Lymph nodes must be 15 mm in short axis when measured by CT or MRI. 
• Patients may have received:
  • NO prior chemotherapy for treatment of endometrial cancer; OR 
  • Prior adjuvant chemotherapy (e.g., paclitaxel/carboplatin alone or as a component of concurrent chemotherapy and radiation therapy [with or without cisplatin]) provided adjuvant chemotherapy was completed  ≥ 12 months prior to STEP 2 registration. 
• Patients may have received prior radiation therapy for treatment of endometrial cancer. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para aortic radiation therapy, and/or intravaginal brachytherapy. All radiation therapy must be completed at least 4 weeks prior to STEP 2 registration. 
• Patients may have received prior hormonal therapy for treatment of endometrial cancer. All hormonal therapy must be discontinued at least three weeks prior to STEP 2 registration. 
• Age ≥ 18 years.
• Performance status of 0, 1 and 2. 
• Hematologic Function:
  • Platelets ≥ 100,000/mcl;
  • Absolute neutrophil count (ANC) ≥ 1,500/mcl.
• Renal Function:
  • Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN).
• Hepatic Function:
  • Total serum bilirubin level ≤ 1.5 x upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN. 
• Thyroid stimulating hormone (TSH) within normal limits (TSH < ULN allowed in euthyroid patients on thyroid replacement therapy). 
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of Step 2 registration are eligible for this trial. 
• For patients of child bearing potential: negative urine or serum pregnancy test within 72 hours prior to Step 2 registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. 
• Administration of study drugs (pembrolizumab, paclitaxel, carboplatin) may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of childbearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from up to 14 days prior to Step 2 registration (for oral contraceptives), during treatment, and for 120 days after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately. Patients will be considered of nonreproductive potential if they are either: 
  • Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy;In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient); OR 
  • Have a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to Step 2 registration; OR 
  • Have a congenital or acquired condition that prevents childbearing. 
• Patients with a prior or current malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessent of the investigational regimen are eligible for this trial
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.

• Patients with prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapeutic antibody or other similar agents.
• Patients who have a history of a severe hypersensitivity reaction to monoclonal antibody or pembrolizumab (MK-3475) and/or its excipients.
• Patients who are currently participating and receiving cancer-directed study therapy or have participated in a study of an investigational agent and received cancer-directed study therapy within 4 weeks prior to Step 2 registration.
• Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to Step 2 registration:
  • Patients who have received steroids as CT scan contrast premedication may be enrolled;
  • The use of inhaled or topical corticosteroids is allowed;
  • The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed;
  • The use of physiologic doses of corticosteroids may be approved after consultation with the study chair.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression, and they have been off steroids for at least 4 weeks prior to Step 2 registration and remain clinically stable.
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. This includes, but is not limited to, patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.
• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• Patients who have a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection (except for uncomplicated UTI), interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; and cirrhosis:
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated;
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Pregnant or lactating patients.

• Male or female age ≥ 18 years.
• Is able and willing to provide written informed consent, which includes compliance with study requirements and restrictions listed in the consent form.
• Have a ≥ 6-month history of documented sarcoidosis including histological confirmation in the subject’s medical records.
• Have high-resolution computed tomography (HRCT) and PET scan consistent with active pulmonary sarcoidosis of the lung parenchyma confirmed by central read.
• Have FVCp ≥ 50% to ≤ 90% and DLCO ≥ 50%.
• If receiving prednisone (or equivalent), dose must have been ≤25 mg, and dose must have been stable for at least 4 weeks prior to randomization.
• Symptomatic as indicated by mMRC Dyspnea scale >1 (i.e., Grade 2 or more) in the prior year.
• If receiving methotrexate and/or other immunosuppressive therapy (IST) dose must have been stable for ≥ 3 months prior to randomization.
• Female subjects must agree to use an approved highly effective birth control (BC) method (< 1% failure rate per year) throughout the study, unless documented to have a reproductive status of non-childbearing potential or is postmenopausal:
  • Non-childbearing potential defined as pre-menopausal female with medical history of bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries), or hysterectomy; hysteroscopic sterilization;
  • Postmenopausal defined as 12 months of spontaneous amenorrhea; otherwise, a follicle stimulating hormone (FSH) confirmation will be required. For females with questionable menopausal history (e.g., irregular menstrual periods and age > 40 years) a documented serum FSH level must be ≥ 30 mIU/mL;
  • Woman of childbearing potential (WCBP) who is already using an established method of highly effective contraception or agrees to use one of the allowed BC methods, for at least 28 days prior to the start of dosing, throughout the study, and for 4 months following the last dose of study drug.
• Males who are sexually active must agree to use one of the allowed BC methods. Male subjects must also agree to sufficiently minimize the risk of pregnancy throughout study participation (and for 4 months following the last dose of study drug).
• Body Mass Index (BMI) 18 to 40 kg/m^2 at screening.
• Subjects must agree to steroid taper, and cessation of their IST therapy at randomization.
• Completion of vaccination for COVID-19 at least 2 weeks prior to randomization.

Exlusion Criteria:

• Hospitalized for any respiratory illness ≤ 30 days prior to screening.
• Prednisone dose > 25 mg/day at any time in the previous 4 weeks.
• ≥ 20% fibrosis as indicated on CT-scan that has been confirmed by central read prior to randomization.
• eGFR ≤30 mL/min/1.73 m^2 (MDRD equation) or requiring hemofiltration or dialysis.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 3 × upper limit of normal range (ULN).
• Platelet count <100,000 per mm^3.
• Hemoglobin ≤ 9.5 g/dL.
• Absolute neutrophil count < 1,000 per mm^3.
• History of known anti-GM-CSF autoAb or tests positive at screening, or history of pulmonary alveolar proteinosis (PAP).
• Use of biologic — approved or investigational agents (e.g., anti-TNFα, anti-IL-1, anti-IL-6, anti-IL-17, anti-IL-12/23 or specific anti-IL-23 inhibitors, anti CD20, anti-IL-18) within the 6 months prior to screening.
• Prior use of immunoglobulin within 6 months prior to screening.
• Prior use of any investigational immunomodulator (e.g., NRP2 modulator) within 6 months of screening.
• Prior use of any JAK inhibitor within 3 months of screening.
• Participation in another interventional clinical trial within 6 months prior to screening.
• Known left ventricular ejection fraction (LVEF) ≤30% or NYHA class III or IV heart failure.
• ECG abnormalities that warrant further investigation, in the opinion of the Investigator.
• Pulmonary hypertension requiring therapy.
• Systolic blood pressure (SBP)  < 90 or > 180 mm Hg; Diastolic blood pressure (DBP) < 60 or > 110 mm Hg.
• Known COVID-19 infection within 3 months prior to screening.
• Have received any live virus or bacterial vaccinations < 3 months of screening. Age-appropriate non-live vaccinations may be administered during screening so long as the last vaccine dose is administered at least 2 weeks prior to planned randomization.
• Any infection requiring antibiotics or pulse of OCS where completion of treatment has been < 30 days prior to screening.
• History of 3 or more lower respiratory tract infections requiring anti-microbial therapy in the past year.
• Any history of mycetoma or fungal respiratory infection.
• Requirement for supplemental oxygen at rest.
• Prior history of, or likely to have any organ transplantation during study including OLE.
• History of smoking (or vaping) in the prior year or current use. Occasional use (defined as less frequently than once per month) is allowable, though subjects should be counseled to remain abstinent during the study including OLE.
• Other significant pulmonary disease likely to interfere with the primary endpoint, in the opinion of the Investigator.
• Other autoimmune disease likely to require therapy during the study.
• Symptoms and features of extra-PS that may warrant treatment in addition to that required for lung involvement.
• Significant ischemic heart disease (i.e., myocardial infarction within 6 months, unstable angina or PCTA/stent within 1 month or planned intervention during study).
• Known or suspected active and untreated/inadequately treated tuberculosis (TB), human immunodeficiency virus (HIV), hepatitis B or C infection. Subjects with latent TB may be enrolled if anti-TB therapy is commenced prior to randomization.
• For women: pregnant or planning to become pregnant during the study or currently breastfeeding.
• Prior history of any malignancy or lymphoproliferative disorder (not including fully resected basal cell carcinoma of the skin, fully resected intra-epithelial neoplasia or carcinoma in situ) within the past 5 years.

Eligibility last updated 12/23/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Women with an initial pathologically confirmed diagnosis of stage I-III, hormone receptor positive, HER2-neu negative, invasive breast cancer within 18 months prior to enrollment.
• Women who have undergone neo-adjuvant chemotherapy who have no residual invasive disease post-surgery are eligible based on an initial pathologically confirmed diagnosis.
• Hormone receptor positive is defined as estrogen receptor (ER) and/or progesterone receptor (PR) of > 1%.
• HER2-neu negative is defined as 0-1+ by immunohistochemical (IHC) analysis, or non-amplified by fluorescence in situ hybridization (FISH) analysis.
• Patients must have received cancer-directed surgery, and/or completed all other adjuvant therapy, except reconstruction.
• Patients must have initiated an endocrine therapy drug within the 6 months prior to registration, OR have received a prescription with stated intent to initiate within 6 weeks after registration.
• No history of previous cancer as follows:
  • Invasive or non-invasive breast cancer at any time.
  • Non-breast cancer, within the past 5 years, excluding non-melanoma skin cancer.
• Patients must be willing to use a smart phone for study activities.
• Patient is NOT to be deemed ineligible during the recruitment process if they do not have a smart phone.
• If a participant does not own a smart phone or has limited data or texting capabilities or their smart phone cannot support the Alliance electronic patient reported outcomes (ePRO) survey application (app), a smart phone and service can be provided to the participant at no cost through the Ohio State University (OSU) partnership with Verizon Wireless for the duration of the study activities.
• The CRP is ONLY to discuss this option with those patients who self-identify a phone-related barrier to participation, including: lack of a smart phone, insufficient phone plan (minutes/text/data), or a smart phone incompatible with the Alliance ePRO app.
• For OSU provided phones, charges will be paid by the grant through the intervention period. At the end of the 12-month intervention period, patients will be responsible for paying monthly fees, if continued service is desired. The physical phones will belong to the patients at the end of their study activities.
• Patients must be willing to use a Pillsy medication event monitoring system for the duration of study participation.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and read English.