• Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the nasopharynx
• Sites are required to complete Step 1 registration before submitting specimens for EBV DNA analysis.
• Patients must have detectable pretreatment plasma EBV DNA, determined by the central lab prior to Step 2 registration (see Section 10.2 for details of specimen submission).
• For patients who have detectable plasma EBV DNA tested at one of the credentialed central labs (listed on the EBV DNA Testing Specimen Transmittal form) within 28 days prior to Step 1 registration: that test result can be used for eligibility without the need for re-testing. To use this test result for eligibility, the central lab must enter the test result through the pathology portal, and the site must follow the instructions in Section 5.4.
• Stage II-IVB disease (AJCC, 7th ed.) with no evidence of distant metastasis, based upon the following minimum diagnostic workup:
• History/physical examination by a Medical Oncologist or Clinical Oncologist or Radiation Oncologist or ENT, which must include an endoscopic evaluation, a complete list of current medications, and assessment of weight and weight loss in the past 6 months within 21 days prior to registration;
• Evaluation of tumor extent required within 28 days prior to registration:
• MRI of the nasopharynx and neck; or CT of the nasopharynx and neck with ≤ 3 mm contiguous slices with contrast and bone windows (to evaluate base of skull involvement). Note: If a treatment planning CT scan is used, it must be with ≤ 3 mm contiguous slices with contrast and be read by a radiologist. Please refer to section 6.3.2 for MRI requirement for target delineation.
• To rule out distant metastasis, patients must undergo the following imaging within 28 days prior to registration: 1. a CT scan with contrast of the chest and abdomen (required), and the pelvis (optional), or a total body PET/CT scan (non-contrast PET/CT is acceptable); 2. a bone scan only when there is suspicion of bone metastases (a PET/CT scan can substitute for the bone scan).
• Zubrod performance status 0-1 within 21 days prior to registration
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable)
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 x institutional ULN
• Alkaline phosphatase ≤ 1.5 x institutional ULN
• Serum creatinine ≤ 1.5 mg/dl or calculated creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour urine collection or estimated by Cockcroft-Gault formula
• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential
• Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control throughout protocol treatment
• Patient must provide study specific informed consent prior to study entry, including the mandatory pre-treatment plasma EBV DNA assay
• Prior invasive malignancy (except node negative, non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; however, at least 6-weeks recovery is necessary if the last regimen included nitrosourea or mitomycin
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Patients with hearing loss assessed to be primarily sensorineural in nature, requiring a hearing aid, or intervention (i.e. interfering in a clinically significant way with activities of daily living); a conductive hearing loss that is tumor-related is allowed
• ≥ Grade 2 peripheral sensory neuropathy (CTCAE, v. 4.0)
• Severe, active co-morbidity, defined as follows:
• Major medical or psychiatric illness, which in the investigator's opinion would interfere with the completion of therapy and follow up or with full understanding of the risks and potential complications of the therapy
• Unstable angina and/or uncontrolled congestive heart failure within the past 6 months
• Myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; note that patients switched from IV antibiotics and currently on oral antibiotics whose infection is assessed to be adequately treated or controlled are eligible
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration
• Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that Human Immunodeficiency Virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Prior allergic reaction to the study drug(s) involved in this protocol
• Patients with undetectable pre-treatment plasma EBV DNA

1. Male or females age 14-18 inclusive 2. Diagnosed with concussion due to sports-related injury. Concussion is defined as: 1. Direct blow to the head, face, neck or a blow elsewhere on the body with an "impulsive" force transmitted to the head. 2. Rapid onset of short-lived impairment of neurologic function in one or more of the following clinical domains that resolves spontaneously: i. Symptoms: somatic (eg, headache), cognitive (eg, feeling like in a fog and/or emotional symptoms (eg, lability). ii. Physical signs (eg, loss of consciousness, amnesia). iii. Behavioral changes (eg, irritability). iv. Cognitive impairment (eg, slowed reaction times). v. Sleep disturbance (eg, drowsiness). c) No abnormality on standard structural neuroimaging studies, if such neuroimaging studies are completed for a clinically-indicated reason. Note: neuroimaging is not a part of this study protocol. Study participants will not undergo neuroimaging as part of this study. 3. Concussion within 4 days of enrollment 4. Presenting for treatment to the Sports Medicine Center at Children's Medical Center 1. Subjects not actively participating in an organized sport at time of enrollment 2. Subjects who received a concussion from an event other than playing a sport (motor vehicle accident, fall, etc.) 3. Subjects who participate in or received a concussion during participation in motorized sports (i.e., motorcross, dirt biking, jet skiing, etc.) 4. Subjects with radiographic evidence of traumatic brain injury (i.e., skull fracture, intracranial hemorrhage, cerebral contusion, etc). 5. Subjects with a prior diagnosed concussion in the previous 6 months. 6. Pregnant women. 7. Subjects sensitive to aspirin 8. Subjects diagnosed with high blood pressure and currently being treated with blood pressure medications 9. Subjects allergic to soy bean oil or corn oil. 10. Subjects currently taking fish oil or DHA supplements.

• infants/ children with midshaft or distal hypospadias undergoing primary single stage repair in one of the Pediatric Regional Anesthesia Network participating centers.
• prior hypospadias surgery,
• proximal or penoscrotal hypospadias,
• abnormal caudal anatomy or spinal dysraphism,
• cyanotic congenital heart disease,
• infection or rash at the block injection site.

• 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 and via the Molecular Characterization Initiative:
• Classical histologic type (non LC/A) WNT medulloblastoma
• Positive nuclear beta-catenin by immunohistochemistry (IHC)
• Positive for CTNNB1 mutation
• Negative for MYC and MYCN by fluorescence in situ hybridization (FISH)
• Patient must have negative lumbar cerebrospinal fluid (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 cm^2 maximal cross-sectional area of residual tumor; whole brain magnetic resonance imaging (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)
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 3 to < 6 years of age: maximum (max) serum creatinine 0.8 mg/dL (males and females)
• 6 to < 10 years of age: max serum creatinine 1 mg/dL (males and females)
• 10 to < 13 years of age: max serum creatinine 1.2 mg/dL (males and females)
• 13 to < 16 years of age: max serum creatinine 1.5 md/dL (males) and 1.4 md/dL (females)
• >= 16 years of age: max serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
• The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC)
• Total or direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [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
• 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, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
• 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
• Pregnancy and Breast Feeding
• 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., intelligence quotient [Q)]=< 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. Children with posterior fossa syndrome (also known as cerebellar mutism) are eligible for this study

Inclusion Criteria Patients will be included if they: 1. are inpatients or outpatients; 2. are voluntary and competent to consent to treatment and research procedures according to ECT/MST attending psychiatrist; 3. have a MINI International Neuropsychiatric Interview diagnosis, Version 6 (MINI-6.0) diagnosis of non-psychotic MDD 4. are 18 years of age or older 5. have a baseline HRSD-24 score > or = 21; 6. are considered to be appropriate to receive convulsive therapy as assessed by an ECT attending psychiatrist and a consultant anaesthesiologist 7. are agreeable to keeping their current antidepressant treatment constant during the intervention; 8. are likely able to adhere to the intervention schedule; 9. meet the MST safety criteria [75]; 10. If a woman of child-bearing potential: is willing to provide a negative pregnancy test and agrees not to become pregnant during trial participation. Exclusion Criteria Patients will be excluded if they: 1. have a history of MINI diagnosis of substance dependence or abuse within the past three months; 2. have a concomitant major unstable medical illness; 3. are pregnant or intend to get pregnant during the study; 4. have a MINI diagnosis of any primary psychotic disorder 5. have a MINI diagnosis of obsessive compulsive disorder, or post-traumatic stress disorder deemed to be primary and causing more functional impairment than the depressive disorder 6. have probable dementia based on study investigator assessment; 7. have any significant neurological disorder or condition likely to be associated with increased intracranial pressure or a space occupying brain lesion, e.g., cerebral aneurysm; 8. present with a medical condition, a medication, or a laboratory abnormality that could cause a major depressive episode or significant cognitive impairment in the opinion of the investigator (e.g., hypothyroidism with low TSH, rheumatoid arthritis requiring high dose prednisone, or Cushing's disease); 9. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed; 10. require a benzodiazepine with a dose > lorazepam 2 mg/day or equivalent or any anticonvulsant due to the potential of these medications to limit the efficacy of both MST and ECT; 11. are unable to communicate in English fluently enough to complete the neuropsychological tests; 12. have a non-correctable clinically significant sensory impairment (i.e., cannot hear or see well enough to complete the neuropsychological tests).

1. New disabling neurological deficit attributable to new ischemic stroke. 2. Minimum lesion diameter of 1.5cm on qualifying imaging. If lesion not visible on imaging, NIHSS must be greater than 4. 3. Non-valvular atrial fibrillation (paroxysmal, persistent, or permanent). 4. Not currently anticoagulated and/or will not be anticoagulated prior to starting their NOAC at the randomized time of initiation (except for DVT prophylaxis). Note: Patients who had been taking an anticoagulant prior to their qualifying index event (for any reason) are eligible for START, assuming the drug is no longer having a therapeutic effect in the patient's system by 48 hours from stroke onset. 5. Treating physician plans to anticoagulate with a FDA-approved novel oral anticoagulant (NOAC): apixaban, dabigatran, edoxaban, or rivaroxaban, or other FDA-approved NOAC. 6. Qualifying brain CT or MRI scan < 48hr from stroke onset (time last known well). If patient has been treated with thrombolytic or endovascular therapy for this stroke, then the qualifying scan is that which is performed after therapy to rule out clinically significant hemorrhagic transformation. 7. Ability to randomize within 60 hours of symptom onset. 1. Any clinical or imaging evidence of spontaneous intracranial hemorrhage in the previous 6 months. Note: Patients with hemorrhagic transformation of current or previous ischemic stroke may be included per Investigator's judgment. Sporadic microbleeds may be included per Investigator's judgment. As a general recommendation, a cerebral microbleed is considered to be ≤ 5mm, but sometimes up to 10mm, in greatest diameter on gradient recalled echo (GRE), or T2*, MRI sequences. Any blood visualized on a CT will be classified as a macrobleed. 2. Infarct volume (estimated) is greater than 50% of middle cerebral artery territory on qualifying scan. If the full extent of the lesion is not visible, any patient with a NIHSS > 23 must be excluded. Note: The lesion does not need to be restricted to the mCA, but if the lesion volume is estimated to be greater than half of the mCA territory, the patient should be excluded. Note: In non-EVT patients, any NIHSS following the index stroke may be used to qualify the patient for START. For example, a patient that presents with a NIHSS of 10 who then receives tPA and improves to a NIHSS of 2 is still eligible for START. For patients whom had endovascular therapy, the qualifying NIHSS assessment is that which is obtained with their qualifying scan following therapy. 3. Anticipated need for major surgery over the next 30 days that would require delay, discontinuation, or extended suspension of anticoagulant of more than 5 days. 4. Symptomatic edema expected from size and location of ischemic stroke. 5. Decreased level of consciousness present or expected. 6. Life expectancy less than 90 days. 7. Follow-up in person or by telephone for 90 days is not feasible.

• Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to enrollment on ANBL1531 (NCT03126916)
• Patient must be >= 365 days and =< 30 years of age at diagnosis
• Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites; the following disease groups are eligible:
• Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features:
• MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of additional biologic features; OR
• Age > 547 days regardless of biologic features
• Patients with INRG stage MS disease with MYCN amplification
• Patients with INRG stage L2 disease with MYCN amplification
• Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS disease who progressed to stage M without prior chemotherapy may enroll within 4 weeks of progression to stage M
• Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1 disease who progress to stage M without systemic therapy may enroll within 4 weeks of progression to stage M
• Patients initially recognized to have high-risk disease must have had no prior systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis and within allowed timing); patients observed or treated with a single cycle of chemotherapy per a low or intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or similar) for what initially appeared to be non-high risk disease but subsequently found to meet the criteria will also be eligible; patients who receive localized emergency radiation to sites of life-threatening or function-threatening disease prior to or immediately after establishment of the definitive diagnosis will be eligible
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows:
• 1 to < 2 years: male = 0.6; female = 0.6
• 2 to < 6 years: male = 0.8; female = 0.8
• 6 to < 10 years: male = 1; female = 1
• 10 to < 13 years: male = 1.2; female = 1.2
• 13 to < 16 years: male = 1.5; female = 1.4
• >= 16 years: male = 1.7; female = 1.4
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x ULN; for the purposes of this study, ULN for SGPT (ALT) is 45
• Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by echocardiogram or radionuclide angiogram
• No known contraindication to peripheral blood stem cell (PBSC) collection; examples of contraindications might be a weight or size less than the collecting institution finds feasible, or a physical condition that would limit the ability of the child to undergo apheresis catheter placement (if necessary) and/or the apheresis procedure
• Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for high risk classification but are not eligible for this trial)
• Patients with bone marrow failure syndromes
• Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to underlying medical disorders
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

•Male or female, age greater than or equal to 45 years at the time of signing informed consent
•Body mass index (BMI) greater than or equal to 27 kg/m^2
•Have established cardiovascular (CV) disease as evidenced by at least one of the following: prior myocardial infarction; prior stroke (ischemic or haemorrhagic stroke); or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) less than 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Exclusion Criteria:
•Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
•HbA1c greater than or equal to 48 mmol/mol (6.5 %) as measured by the central laboratory at screening
•History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)

• The patient must sign consent for study participation.
• The patient must be female and have a diagnosis of an invasive or non-invasive breast cancer that was treated surgically by a partial mastectomy.
• The patient must be deemed an appropriate candidate for breast conserving therapy (i.e. not pregnant, never had radiation to the treated breast, breast size would allow adequate cosmesis after volume loss from partial mastectomy).
• Patients with involved lymph nodes are candidates for the study.
• Surgical margins are negative for invasive (no tumor on ink) or non-invasive breast cancer (2 mm negative margin).
• The greatest dimension of the tumor is less than 4cm before surgery.
• Multifocal disease is allowed if it was removed by a single lumpectomy resection and the patient remained a candidate for breast conservation.
• Age 18 years and older.
• Women of childbearing potential (pre-menopausal defined as having a menstrual period within the past 1 year) must have a negative serum pregnancy test or complete a pregnancy waiver form per institutional policy.
• The surgical cavity is clearly visible on CT images. Of note, clips are not required but recommended.
• The patient must weigh less than 150Kg (330lb), which is the limit of the imaging couch.
• The patient must be less than 6'6" in height.
• The patient must feel comfortable in the prone position.
• Diagnosis of prior contralateral breast cancer is allowed.
• Diagnosis of synchronous bilateral cancers is allowed. In this case if bilateral boosts are required, a patient would not have both treatments on the same day.
• Oncoplastic reduction surgery is allowed if the lumpectomy cavity can be clearly visualized.
• Patients with proven multi-centric carcinoma (tumors in different quadrants of the breast or tumor separated by at least 4 cm).
• Prior radiation therapy to that breast or that hemi thorax.
• Unable to fit into the immobilization breast cup with an adequate seal.
• Male gender.
• Patient cannot comfortably be set up in the prone position (i.e. physical disability)
• Unable to fit into the breast immobilization device due to breast size or other anatomical reason.
• Mastectomy is the surgery performed.
• Patient has received prior radiotherapy to the involved breast.
• Tumor bed is less than 3 mm from the skin surface.
• Greater than 50% of the target volume is above the upper border of the table.
• Patients with skin involvement, regardless of tumor size.
• Patients with connective tissue disorders specifically systemic lupus erythematosis, scleroderma, or dermatomyositis.
• Patients with psychiatric or addictive disorders that would preclude obtaining informed consent.
• Patients who are pregnant or lactating due to potential exposure of the fetus to RT and unknown effects of RT to lactating females.
• Patients with breast implants/tissue expanders or flap reconstruction.

• Patients with histologically proven GBM
• Newly diagnosed GBM. Prior surgery is allowed, but should not have started any other treatment such as chemotherapy, radiation treatment, and anti-angiogenic therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Women of child-bearing potential must agree to undergo a urine pregnancy screening per standard Radiology departmental protocol, in place to prevent imaging of pregnant patients. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 1) Has not undergone a hysterectomy or bilateral oophorectomy; or 2) Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Scheduled to undergo chemoradiation.
• Subjects who have had prior chemotherapy or radiotherapy.
• Subjects may not be receiving any other investigational agents at the time of enrollment.
• Subjects must not be pregnant since pregnancy is a contraindication to administration of gadolinium-based contrast agents.
• Any contraindication to MRI per Radiology Department's routine protocol, e.g. MRI-incompatible objects, including but not limited to medical devices (e.g. pacemakers, automated implantable cardioverter defibrillators, etc.) and other foreign bodies.
• Known severe allergic reaction to Gadolinium-based contrast agents.
• Patients with sickle cell disease and patients with other hemolytic anemias (low red blood count in body).
• Patients with uncontrollable claustrophobia, severe lower back pain, and uncontrollable tremors, to the point that it would render them unable to tolerate an MRI study.

Inclusion: 1. Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging. 2. Age ≥2 and <21 years at the time of study entry. 3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age. 4. Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed). 5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits. 6. Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome. 7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component). 8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia. 9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit. Exclusion: 1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible. 2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. 3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.) 4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 5. Prior irradiation to >50% of the bone marrow (see Appendix 9). 6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry. 7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries. 8. For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX. 9. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days. 10. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable. 11. Hereditary bone marrow failure disorder. 12. QTc >470 msec. 13. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%. 14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy). 15. Severe acute or chronic medical or laboratory test 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 patient inappropriate for entry into this study. 16. 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 patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.

• Patient must be >= 18 years of age
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, or 2 (However, those patients with a performance state of 3 because they are wheel chair bound due to congenital or traumatic events more than one year before the diagnosis of Merkel cell carcinoma are eligible).
• Patient must have a histological confirmation of diagnosis of Merkel cell carcinoma (MCC), pathologic stages (American Joint Committee on Cancer [AJCC] version 8) I-IIIb.
• Stage I patients with negative sentinel lymph node biopsy are ineligible. Patients who have a positive biopsy or for whom no biopsy was done are eligible.
• Patients with distant metastatic disease (stage IV) are ineligible.
• The primary tumor must have grossly negative margins. (Microscopically positive margins are allowed).
• Cancers of unknown primary that have regional disease only are eligible.
• Complete nodal dissection is not required for eligibility.
• Patients with all macroscopic Merkel cell carcinoma (either identified by physical exam or imaging) have been completely resected by surgery within 16 weeks before randomization.
• All patients must have disease-free status documented by a complete physical examination and conventional imaging studies within 8 weeks prior to randomization.
• Patient may not have a history of distant metastatic disease.
• NOTE: Loco-regional recurrent disease is acceptable, as long as this is not metastatic (prior surgery with or without radiation therapy is acceptable).
• For patients with initial presentation of Merkel cell carcinoma, patient must have no previous systemic therapy or radiation therapy prior to surgery for Merkel cell carcinoma and cannot have completed adjuvant radiation therapy for Merkel cell carcinoma more than 6 weeks prior to randomization. Patients actively undergoing radiation therapy or having completed adjuvant radiation therapy within 6 weeks of randomization are eligible, as long as resection date is within 16 weeks of randomization. Patients with prior radiation at a non-Radiation Oncology Core (IROC) provider are eligible for the trial. If the patient has not received radiation, and treatment at a Radiation Oncology Core (IROC) provider is not possible, the patient can start and complete radiation prior to randomization, with recommendations to follow radiation protocol guidelines with submission of treatment records.
• White blood count >= 2000/uL (within 4 weeks prior to randomization).
• Absolute neutrophil count (ANC) >= 1000/uL (within 4 weeks prior to randomization).
• Platelets >= 75 x 10^3/uL (within 4 weeks prior to randomization).
• Hemoglobin >= 8 g/dL (>= 80 g/L; may be transfused) (within 4 weeks prior to randomization).
• Creatinine =< 2.0 x institutional upper limit of normal (ULN) (within 4 weeks prior to randomization).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN (within 4 weeks prior to randomization).
• Total bilirubin =< 2.0 x institutional ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL) (within 4 weeks prior to randomization).
• Patients who are human immunodeficiency virus (HIV)+ with undetectable HIV viral load are eligible provided they meet all other protocol criteria for participation.
• Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are eligible provided viral loads are undetectable. Patients on suppressive therapy are eligible.
• Patient must not be pregnant or breast-feeding due to the unknown effects of the study drug in this setting. All patients of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy. A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Patients on Arm A MK-3475 (Pembrolizumab) must not conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment. For patients on Arm B only receiving radiation therapy, contraception use should be per institutional standard.
• Patients must not be on active immunosuppression, have a history of life threatening virus, have had other (beside non-melanoma skin cancers, or recent indolent cancers e.g.: resected low grade prostate cancer) invasive cancer diagnoses in the last two years, or have had immunotherapy of any kind within the last 2 years prior to randomization.
• Patients must not have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Operative notes from patient's surgical resection must be accessible.

1. CD19 expressing B-cell Acute Lymphoblastic Leukemia 2. De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC. EOC bone marrow MRD will be collected prior to screening and will be assessed by multi-parameter flow cytometry using central laboratory analysis. 3. Age 1 to 25 years at the time of screening 4. Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60% 5. Adequate organ function during the screening period: A. Renal function based on age/gender B. ALT ≤ 5 times ULN for age C. AST ≤ 5 times ULN for age D. Total bilirubin < 2 mg/dL (for Gilbert's Syndrome subjects total bilirubin < 4 mg/dL) E. Adequate pulmonary function defined as:
• no or mild dyspnea (≤ Grade 1)
• oxygen saturation of > 90% on room air F. Adequate cardiac function defined as LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram or MUGA within 6 weeks of screening 6. Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3 blocks of standard chemotherapy for first-line B-ALL, defined as 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance with high-dose methotrexate. 1. M3 marrow at the completion of 1st line induction therapy 2. M2 or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy or evidence of disease progression in the peripheral blood or new extramedullary disease prior to enrollment. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia at the time of screening. 3. Philadelphia chromosome positive ALL 4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone 5. Prior tyrosine kinase inhibitor therapy 6. Subjects with concomitant genetic syndromes associated with bone marrow failure states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Subjects with Down syndrome will not be excluded. 7. Subjects with Burkitt's lymphoma/leukemia (i.e. subjects with mature B-ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation) 8. Has had treatment with any prior anti-CD19 therapy 9. Treatment with any prior gene or engineered T cell therapy Other protocol-defined inclusion/exclusion may apply.

• Age Patients must be ≤21 years of age at the time of enrollment. 1. Phase 1
•Initial enrollment will be restricted to patients < 18 years of age until 9 such patients are enrolled 2. Phase 2
•Initial enrollment will be restricted to patients < 18 years of age until 6 such patients are enrolled
• Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype ALL or mature B (Burkitt-like) leukemia are not eligible. 1. Patients with ALL must have ≥ 5% blasts by morphology. 2. Patients with LLy must have measurable disease documented by clinical, radiologic or histologic criteria
• Performance Level Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age.
• Prior Therapy A. Prior therapeutic attempts
• Phase 1
•Any patients with relapsed/refractory ALL or LLy
• Phase 2 1. B-cell ALL/LLy: all patients must have failed two or more therapeutic attempts. 2. T-cell ALL/LLy: all patients must have failed one or more therapeutic attempts. B. Recent prior chemotherapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy.
• Patients who relapsed while they are receiving cytotoxic therapy At least 14 days must have elapsed since the completion of the last dose of chemotherapy,except Intrathecal chemotherapy, and/or maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids. There is no waiting period for those relapsing on maintenance therapy. C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days post-transplant at the time of enrollment. D. Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with G-CSF or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®). E. Biologic (anti-neoplastic agent): At least 7 days since the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair 1. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody. (i.e., blinatumomab = 6 hours,44 inotuzumab = 37 days, rituximab = 66 days) 2. Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g., tumor vaccines, CAR T cells. F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to any extramedullary site other than CNS; ≥90 days must have elapsed if prior total body irradiation (TBI) or craniospinal XRT. G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin equivalents of anthracyclines. H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g., bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a partial response to a proteasome inhibitor with chemotherapy combination. -Renal and hepatic function Patients must have adequate renal and hepatic functions as indicated by the following laboratory values: A. Adequate renal function defined as: Patient must have a calculated creatinine clearance or radioisotope GFR 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase (ALT) ≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved by the study chair or vice chair.
• Adequate Cardiac Function Defined as: Shortening fraction of more than or equal to 27% by echocardiogram, OR ejection fraction of equal to or more than 50% by radionuclide angiogram (MUGA).
• Reproductive Function A. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment. B. Female patients with infants must agree not to breastfeed their infants while on this study. C. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.
• Informed Consent Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines. To allow non-English speaking patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible.
• All institutional, FDA, and OHRP requirements for human studies must be met. Patients will be excluded if they have isolated CNS or testicular disease. Patients will be excluded if they have ≥grade 2 peripheral sensory or motor neuropathy (defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of enrollment (see section 4.7.1.1). Patients will be excluded if they have a known allergy or intolerance to any of the drugs used in the study
•except for PEG-asparaginase for which erwinia asparaginase may be substituted Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period. Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results. Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded. Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin equivolents of anthracyclines (anthracycline equivalence to doxorubicin conversion see appendix iv) . Concomitant medications Investigational drugs: Patients currently receiving another investigational drug are not eligible. Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant are not eligible. CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of CYP3A4 are not eligible. Strong inducers of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. See appendix ii for a list of agents which fall into this category. Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy Infants or Patients with Down Syndrome will be excluded in phase 2 of the study

• Participant is currently diagnosed with and/or being treated for secondary hyperparathyroidism (SHPT).
• Participant must be diagnosed with chronic kidney disease (CKD) stage 5 receiving peritoneal dialysis (PD) or hemodialysis (HD) for at least 30 days prior to initial Screening.
• For entry into the Washout Period (for vitamin D receptor activator [VDRA] non-naive participants), the participant must meet the appropriate laboratory criteria based upon the participant's age as described in the protocol.
• For entry into the Dosing Period (for VDRA-naive participants or VDRA non-naive participants who have completed the Washout Period), the participant must meet the appropriate laboratory criteria based upon the participant's age as described in the protocol.
• Participant is expected or scheduled to receive a kidney transplant within 6 months of Screening or is a kidney transplant recipient.
• Participant is expected to discontinue peritoneal dialysis (PD) or hemodialysis (HD) within 6 months of the initial Screening visit.
• Participant has had a parathyroidectomy within 12 weeks prior to Screening.
• Participant is taking maintenance calcitonin, bisphosphonates, glucocorticoids (in a dose equivalent to more than > 0.16 mg/kg/day or 5 mg prednisone/day, whichever is lower), 4 weeks prior to Dosing.
• Participant is receiving calcimimetics at the time of Screening or is expected to initiate calcimimetics at any time throughout the study.
• Participant is unable to take oral medications.

• B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility studies (Part A) prior to treatment and enrollment on AALL1732. Note that central confirmation of MPAL diagnosis must occur within 22 business days after enrollment for MPAL patients. If not performed within this time frame, patients will be taken off protocol.
• APEC14B1 is not a requirement for B-LLy patients but for institutional compliance every patient should be offered participation in APEC14B1. B-LLy patients may directly enroll on AALL1732.
• Patients must be > 365 days and < 25 years of age
• White blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to the start of protocol-directed systemic therapy):
• Age 1-9.99 years: WBC >= 50,000/uL
• Age 10-24.99 years: Any WBC
• Age 1-9.99 years: WBC < 50,000/uL with:
• Testicular leukemia
• CNS leukemia (CNS3)
• Steroid pretreatment.
• White blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to the start of protocol-directed systemic therapy):
• Age 1-24.99 years: any WBC.
• Patient has newly diagnosed B-ALL or MPAL (by World Health Organization [WHO] 2016 criteria) with >= 25% blasts on a bone marrow (BM) aspirate;
• OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM biopsy;
• OR A complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells if a bone marrow aspirate or biopsy cannot be performed.
• Patient has newly diagnosed B-LLy Murphy stages III or IV.
• Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment.
• Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met.
• Patients with Down syndrome are not eligible (patients with Down syndrome and B-ALL are eligible for AALL1731, regardless of NCI risk group).
• With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1732.
• Patients who have received > 72 hours of hydroxyurea within one week prior to start of systemic protocol therapy.
• Patients with B-ALL or MPAL who do not have sufficient diagnostic bone marrow submitted for APEC14B1 testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
• Patients with acute undifferentiated leukemia (AUL) are not eligible.
• For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid pretreatment, the following additional exclusion criteria apply:
• T-lymphoblastic lymphoma.
• Morphologically unclassifiable lymphoma.
• Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
• Patients with known Charcot-Marie-Tooth disease.
• Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
• Patients requiring radiation at diagnosis.
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating women who plan to breastfeed their infants while on study and for 2 months after the last dose of inotuzumab ozogamicin.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of study participation. For those patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the last dose of inotuzumab ozogamicin for females and 5 months after the last dose of inotuzumab ozogamicin for males.

1. Prior SOT of kidney, liver, heart, lung, pancreas, small bowel, or any combination of these (SOT cohort); or prior allogeneic HCT (HCT cohort) 2. A diagnosis of locally-assessed, biopsy-proven EBV+ PTLD 3. Availability of appropriate partially HLA-matched and restricted tabelecleucel has been confirmed by the sponsor 4. Measurable, 18F-deoxyglucose (FDG)-avid (Deauville score ≥ 3) systemic disease using Lugano Classification response criteria by positron emission tomography (PET)-diagnostic computed tomography (CT), except when contraindicated or mandated by local practice, then magnetic resonance imaging (MRI) may be used.For subjects with treated central nervous system (CNS) disease, a head CT and/or brain/spinal MRI as clinically appropriate will be required to follow CNS disease response per Lugano Classification response criteria. 5. Treatment failure of rituximab or interchangeable commercially available biosimilar monotherapy (SOT subgroup A or HCT cohort) or rituximab plus any concurrent or sequentially administered chemotherapy regimen (SOT subgroup B) for treatment of PTLD. 6. Eastern Cooperative Oncology Group performance status ≤ 3 for subjects aged ≥ 16 years; Lansky score ≥ 20 for subjects < 16 years 7. For HCT cohort only: If allogeneic HCT was performed as treatment for an acute lymphoid or myeloid malignancy, the underlying primary disease for which the subject underwent transplant must be in morphologic remission 8. Adequate organ function 1. Absolute neutrophil count ≥ 1000/μL, (SOT cohort) or ≥ 500/μL (HCT cohort), with or without cytokine support 2. Platelet count ≥ 50,000/μL, with or without transfusion or cytokine support. For HCT cohort, platelet count < 50,000/μL but ≥ 20,000/μL, with or without transfusion support, is permissible if the subject has not had grade ≥ 2 bleeding in the prior 4 weeks (where grading of the bleeding is determined per the National Cancer Institute's Common Terminology Criteria for Adverse Events [CTCAE], version 5.0) 3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin each < 5 × the upper limit of normal; however, ALT, AST, and total bilirubin each ≤ 10 × upper limit of normal is acceptable if the elevation is considered by the investigator to be due to EBV and/or PTLD involvement of the liver as long as there is no known evidence of significant liver dysfunction 9. Subject or subject's representative is willing and able to provide written informed consent 1. Burkitt lymphoma, classical Hodgkin lymphoma, or any T cell lymphoma 2. Daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis 3. Untreated CNS PTLD or CNS PTLD for which the subject is actively receiving CNS-directed chemotherapy (systemic or intrathecal) or radiotherapy at enrollment. NOTE:Subjects with previously treated CNS PTLD may enroll if CNS-directed therapy is complete. 4. Suspected or confirmed grade ≥ 2 graft-versus-host disease (GvHD) per the Center for International Blood and Marrow Transplant Research consensus grading system at enrollment 5. Ongoing or recent use of a checkpoint inhibitor agent (eg, ipilimumab, pembrolizumab, nivolumab) within 3 drug half-lives from the most recent dose to enrollment 6. For HCT cohort: active adenovirus viremia 7. Need for vasopressor or ventilatory support 8. Antithymocyte globulin or similar anti-T cell antibody therapy ≤ 4 weeks prior to enrollment 9. Treatment with Epstein-Barr virus cytotoxic T lymphocytes or chimeric antigen receptor T cells directed against B cells within 8 weeks of enrollment (SOT or HCT cohorts), or unselected donor lymphocyte infusion within 8 weeks of enrollment (HCT cohort only) 10. Female who is breastfeeding or pregnant or female of childbearing potential or male with a female partner of childbearing potential unwilling to use a highly effective method of contraception 11. Inability to comply with study-related procedures

• Patients must be >= 2 years and =< 21 years at the time of enrollment
• Patients must have a body surface area (BSA) of >= 0.5 m^2 at enrollment
• Patients must have neurofibromatosis type 1 (NF1) based on clinical criteria and/or germline genetic testing
• Patients must be newly diagnosed or have previously diagnosed NF-1 associated LGG that has not been treated with any modality other than surgery
• For patients with optic pathway gliomas (OPGs):
• Newly-diagnosed patients with OPG are eligible if there are neurologic symptoms (including visual dysfunction, as defined below) or other exam findings associated with the tumor
• Previously-diagnosed patients with OPG are eligible if they have new or worsening neurologic symptoms (including visual dysfunction, as defined below) or have tumor growth
• For both newly-diagnosed and previously-diagnosed OPG, the patient may be eligible, irrespective of whether there has been tumor growth or other neurological symptoms or worsening, if they meet at least one of the following visual criteria:
• Visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year (by examination or history); OR
• Significant visual dysfunction (defined as VA worse than normal for age by 0.6 logMAR [20/80, 6/24, or 2.5/10] or more in one or both eyes)
• For patients with LGG in other locations (i.e., not OPGs):
• Newly-diagnosed patients with LGG are eligible if there are neurologic symptoms or other exam findings associated with the tumor
• NOTE: Newly-diagnosed patients with LGG without associated neurologic symptoms or exam findings are not eligible
• Previously-diagnosed patients with LGG are eligible if they have new or worsening neurologic symptoms or have tumor growth
• Although not required, if a biopsy/tumor resection is performed, eligible histologies will include all tumors considered LGG or low-grade astrocytoma (World Health Organization [WHO] grade I and II) by 5th edition WHO classification of central nervous system (CNS) tumors with the exception of subependymal giant cell astrocytoma
• Patients must have two-dimensional measurable tumor >= 1 cm^2
• Patients with metastatic disease or multiple independent primary LGGs are allowed on study
• Creatinine clearance or radioisotope glomerular filtration Rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender (within 7 days prior to enrollment) as follows:
• Age; maximum serum creatinine (mg/dL)
• 2 to < 6 years; 0.8 (male) and 0.8 (female)
• 6 to < 10 years; 1 (male) and 1 (female)
• 10 to < 13 years; 1.2 (male) and 1.2 (female)
• 13 to < 16 years; 1.5 (male) and 1.4 (female)
• >= 16 years; 1.7 (male) and 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment) (children with a diagnosis of Gilbert's syndrome will be allowed on study regardless of their total and indirect [unconjugated] bilirubin levels as long as their direct [conjugated] bilirubin is < 3.1 mg/dL)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN) = 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L
• Albumin >= 2 g/dL (within 7 days prior to enrollment)
• Left ventricular ejection fraction (LVEF) >= 53% (or institutional normal; if the LVEF result is given as a range of values, then the upper value of the range will be used) by echocardiogram (within 4 weeks prior to enrollment)
• Corrected QT (QTc) interval =< 450 msec by electrocardiography (EKG) (within 4 weeks prior to enrollment)
• Absolute neutrophil count >= 1,000/uL (unsupported) (within 7 days prior to enrollment)
• Platelets >= 100,000/uL (unsupported) (within 7 days prior to enrollment)
• Hemoglobin >= 8 g/dL (may be supported) (within 7 days prior to enrollment)
• Patients with a known seizure disorder should be stable and should have not experienced a significant increase in seizure frequency within 2 weeks prior to enrollment
• Patients 2-17 years of age must have a blood pressure that is =< 95th percentile for age, height, and gender at the time of enrollment. Patients >= 18 years of age must have a blood pressure =< 130/80 mmHg at the time of enrollment (with or without the use of antihypertensive medications).
• Note: Adequate blood pressure can be achieved using medication for the treatment of hypertension
• All patients must have ophthalmology toxicity assessments performed within 4 weeks prior to enrollment
• For all patients, an MRI of the brain (with orbital cuts for optic pathway tumors) and/or spine (depending on the site(s) of primary disease) with and without contrast must be performed within 4 weeks prior to enrollment
• For patients who undergo a surgery on the target tumor (not required), a pre- and post-operative* MRI of the brain (with orbital cuts for optic pathway tumors) or spine (depending on the site(s) of primary disease) with and without contrast must also be performed within 4 weeks prior to enrollment
• The post-operative MRIs should be performed ideally within 48 hours after surgery if possible
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Patients must have the ability to swallow whole capsules
• Patients must have receptive and expressive language skills in English or Spanish to complete the quality of life (QOL) and neurocognitive assessments
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant. Prior surgical intervention is permitted
• Patients with a concurrent malignancy or history of treatment (other than surgery) for another tumor within the last year are ineligible
• Patients may not be receiving any other investigational agents
• Patients with any serious medical or psychiatric illness/ condition, including substance use disorders likely in the judgement of the investigator to interfere or limit compliance with study requirements/treatment are not eligible
• Patients who, in the opinion of the investigator, are not able to comply with the study procedures are not eligible
• Female patients who are pregnant are not eligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants are not eligible
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 12 weeks after stopping study therapy are not eligible
• Note: Women of child-bearing potential and males with sexual partners who are pregnant or who could become pregnant (i.e., women of child-bearing potential) should use effective methods of contraception for the duration of the study and for 12 weeks after stopping study therapy to avoid pregnancy and/or potential adverse effects on the developing embryo
• Cardiac conditions:
• Known genetic disorder that increases risk for coronary artery disease. Note: The presence of dyslipidemia in a family with a history of myocardial infarction is not in itself an exclusion unless there is a known genetic disorder documented
• Symptomatic heart failure
• New York Heart Association (NYHA) class II-IV prior or current cardiomyopathy
• Severe valvular heart disease
• History of atrial fibrillation
• Ophthalmologic conditions:
• Current or past history of central serous retinopathy
• Current or past history of retinal vein occlusion or retinal detachment
• Patients with uncontrolled glaucoma
• If checking pressure is clinically indicated, patients with intraocular pressure (IOP) > 22 mmHg or ULN adjusted by age are not eligible
• Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN), such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
• Treatments and/or medications patient is receiving that would make her/him ineligible, such as:
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
• Surgery within 2 weeks prior to enrollment, with the exception of surgical placement for vascular access or cerebrospinal fluid (CSF) diverting procedures such as endoscopic third ventriculostomy (ETV) and ventriculo-peritoneal (VP) shunt.
• Note: Patients must have healed from any prior surgery prior to enrollment
• Patients who have an uncontrolled infection are not eligible

1. Has 3 office blood pressure measurements with a mean office systolic blood pressure (SBP) of ≥150 mmHg and ≤180 mmHg, AND a mean office diastolic blood pressure (DBP) of ≥90 mmHg when receiving 2 to 5 antihypertensive medications. 2. Has a mean 24-hour ambulatory SBP of ≥135 mmHg and ≤170 mmHg with ≥70% valid readings 1. Subject has renal artery anatomy abnormalities. 2. Subject has an estimated glomerular filtration rate (eGFR) of ≤45 mL/min/1.73 m2, based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; or is on chronic renal replacement therapy. 3. Subject has documented sleep apnea. 4. Subject has any of the following conditions: severe cardiac valve stenosis, heart failure (New York Heart Association [NYHA] Class III or IV), chronic atrial fibrillation, and known primary pulmonary hypertension (>60 mmHg pulmonary artery or right ventricular systolic pressure). 5. Subject is pregnant or lactating at the time of enrollment or planning to become pregnant during the trial time period (female subjects only). 6. Subject is being treated chronically (e.g. daily use) with NSAIDs, immunosuppressive medications, or immunosuppressive doses of steroids. Aspirin therapy and nasal pulmonary inhalants are allowed. 7. Subject has a history of myocardial infarction, unstable angina pectoris, or stroke/TIA within 6 months prior to the planned procedure.

Newly Diagnosed
• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
• Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from definitive surgery or biopsy. Recurrent
• Age ≥ 18 years.
• Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry [IHC] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
• Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
• Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
• Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
• Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed. Newly Diagnosed
• Received any prior treatment for glioma including: a. Prior prolifeprospan 20 with carmustine wafer. b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent. c. Prior radiation treatment for GBM or lower-grade glioma. d. Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Recurrent
• Early disease progression prior to 3 months (12 weeks) from the completion of RT.
• More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy.)
• Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
• Any prior treatment with prolifeprospan 20 with carmustine wafer.
• Any prior treatment with an intracerebral agent.
• Receiving additional, concurrent, active therapy for GBM outside of the trial
• Extensive leptomeningeal disease.
• QTc > 450 msec if male and QTc > 470 msec if female.
• History of another malignancy in the previous 2 years, with a disease-free interval of < 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

Inclusion Criteria
• Males and females ≥40 to ≤80 years of age
• Subject is able to read, understand, and sign a written Informed Consent in order to participate in the Study
• Subject has a diagnosis of chronic bronchitis (CB) and/or chronic obstructive pulmonary disease (COPD) for a minimum of two years. (Chronic Bronchitis is defined clinically as chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes of productive cough have been excluded)
• Subject is classified as having a moderate or severe (GOLD 2/3) airflow obstruction defined by a post-bronchodilator of ≥30% FEV1 to <80% predicted with a baseline FEV1/FVC of <0.70
• Subject has a Baseline SGRQ of ≥50
• Subject demonstrates daily cough and significant mucus.
• Subject is being treated according to current medically accepted treatment guidelines for chronic bronchitis for minimum of 3 months prior to enrollment into the study. Subject agrees to continue maintenance pulmonary/COPD medications (GOLD standard medications recommended) for the duration of the study
• Non-smoking for a minimum of 2 months prior to consent and agrees to continue not smoking for the duration of the study
• Subject is able to adhere to and undergo 2 bronchoscopic procedures (cross over subjects may undergo two additional bronchoscopic procedures, if they agree to treatment), per hospital guidelines
• Subject demonstrates ability and willingness to use a daily eDiary Exclusion Criteria
• Subject has had an acute pulmonary infection, exacerbation or pneumonia requiring medical treatment (with antibiotics and/or steroids) within 4 weeks prior of initially planned study bronchoscopy
• Current diagnosis of Asthma
• Subject has Alpha-1 antitrypsin deficiency as defined by blood level <59 mg/dL
• Subject has other origins of respiratory disease aside from chronic bronchitis and COPD
• Subject is using e-cigarettes, vaping or taking any inhaled substances not prescribed by a physician
• Subject has untreatable or life threatening arrhythmias, inability to adequately oxygenate during the bronchoscopy, or has acute respiratory failure
• Subject has bullous emphysema characterized as large bullae >30 millimeters on HRCT; or subject has stenosis in the tracheobronchial system, tracheobronchomegaly, trachea-bronchomalacia, amyloidosis or cystic fibrosis
• Subject has clinically significant bronchiectasis
• Subject has had a solid transplant procedure
• Subject has a known mucosal tear, has undergone prior lung surgery such as pneumonectomy, lobectomy, bullectomy, or lung volume reduction surgery
• Subject has had a prior lung device procedure, including emphysema stent(s) implanted, lung coils, valves, lung denervation, bronchial thermoplasty, cryotherapy or other therapies
• Subject is unable to temporarily discontinue use of anticoagulant therapy: warfarin, Coumadin, LMWH, heparin, clopidrogel (or equal)
• Subject has a serious medical condition, such as: uncontrolled coagulopathy or bleeding disorder, congestive heart failure, uncontrolled angina, myocardial infarction in the past year, renal failure, liver disease, cerebrovascular accident within the past 6 months, uncontrolled diabetes, uncontrolled hypertension or uncontrolled gastric reflux
• Subject is pregnant, nursing, or planning to get pregnant during study duration
• Subject has or is receiving chemotherapy or active radiation therapy within the past 6 months or is expected to receive chemotherapy during participation in this study
• Subject is or has been in another treatment study within 6 weeks of enrollment and agrees to not participate in any other treatment studies for the duration of study participation
• Subject has known sensitivity to medication required to perform bronchoscopy (such as lidocaine, atropine, and benzodiazepines)

• Recently diagnosed with prostate cancer for whom definitive surgical treatment is indicated
• Not suitable to undergo MRI or receive gadolinium-based contrast agent (severe, untreatable claustrophobia; MRI-incompatible metallic objects or implanted medical devices; renal failure; weight greater than allowable by scanner per institutional standard practice)
• Prior surgical and/or non-surgical treatment for prostate cancer
• Prior hip replacement or other major pelvic surgery

• Patient must have histologically proven T1-2N0M0 invasive anal canal or anal margin squamous cell carcinoma with tumors measuring =< 4 cm within 4 weeks prior to randomization. This may include tumors of non-keratinizing histology such as basaloid, transitional cell or cloacogenic histology. Patients with T1N0M0 anal margin squamous cell carcinoma who underwent surgical excision with negative margins are not eligible
• Patients who are human immunodeficiency virus (HIV)-negative must not have lymph nodes that are radiographically-concerning for cancer involvement using computed tomography (CT) and positron emission tomography (PET)/CT-based criteria. Measurable disease is not required
• Patients who are HIV-negative and do not have lymph nodes classified as lymph node positive, but are felt to be borderline for cancer involvement must undergo central imaging review
• NOTE: Patients requiring central imaging review will be pre-registered to Arm S. Upon central confirmation of no lymph node involvement, eligible patients may proceed to randomization on Step 1
• Patients will be considered to be lymph node (LN) positive and thereby not eligible in this study if the lymph nodes meet any of the following criteria:
• Mesorectal, presacral, internal iliac or obturator LN with:
• Short axis measuring > 5 mm based on CT / magnetic resonance imaging (MRI) OR
• Morphologic features of irregular border or central necrosis if assessed on MRI and LN measures > 3 mm OR
• Fludeoxyglucose F-18 (FDG) uptake > blood pool (Deauville 3-5) based on PET/CT
• External Iliac and common Iliac:
• Short-axis measuring > 1 cm based on CT / MRI OR
• Morphologic features of irregular border or central necrosis based on CT / MRI OR
• FDG uptake > blood pool (Deauville 3-5) based on PET/CT
• Inguinal LN (superficial and deep) meeting any of the following criteria will be ineligible unless an FNA is performed and resulting cytology is negative.
• Morphologic features of irregular border or central necrosis based on CT / MRI
• FDG uptake > liver (Deauville 4) based on PET/CT.
• Patients who are HIV-negative and have inguinal lymph nodes that do not meet the above criteria must undergo fine needle aspiration and have negative histology to be eligible.
• Patients who are HIV-positive must have
• A CD4 count >= 300
• Confirmation of no lymph node involvement by central real-time review of imaging
• NOTE: Patients will be pre-registered to Arm S. Upon central confirmation of no lymph node involvement, eligible patients may proceed to randomization on Step 1
• Patient must have Eastern Cooperative Oncology Group (ECOG)
•American College of Radiology Imaging Network (ACRIN) performance status of 0-2
• Patient must have no history of prior radiation or chemotherapy for this malignancy
• Patient must not have had prior potentially curative surgery (i.e. abdominal-perineal resection) for carcinoma of the anus
• Patients with excisional biopsy procedure are eligible provided there was tumor involvement of the anal canal and/or anal verge prior to resection
• Patient must not be receiving any other standard anti-cancer therapy or experimental agent concurrently with the study drugs
• Patient must not have intercurrent illness including, but not limited to, ongoing or active infection or psychiatric/social situations that, in the judgement of the investigator, would limit compliance with study requirements
• Patient must not have had significant cardiovascular disease including myocardial infarction, unstable angina, stroke, transient ischemic attack, symptomatic coronary artery disease, symptomatic congestive heart failure, or uncontrolled cardiac arrhythmia within 6 months of randomization
• Patient must not have a history of a different malignancy unless they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk of recurrence
• Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ and basal cell or squamous cell carcinoma of the skin
• Patient must not have active autoimmune or connective disease
• Patients who are on anti-coagulation with warfarin within 2 weeks prior to registration and are considering the use of capecitabine, must use an alternative anti-coagulant
• NOTE: Low molecular weight heparin is permitted provided the patient's prothrombin time (PT)/international normalized ratio (INR) is < 1.5
• Patients who will receive capecitabine and are on Dilantin for a seizure disorder must have Dilantin levels checked weekly
• Hemoglobin > 10 g/dL (within 2 weeks prior to registration)
• Platelets >= 100,000/mm^3 (within 2 weeks prior to registration)
• Absolute neutrophil count >= 1500/mm^3 (within 2 weeks prior to registration)
• Serum creatinine must be < 1.5 X upper limit of normal (ULN), or calculated creatinine clearance must be > 60 ml/min (within 2 weeks prior to registration)
• Total bilirubin must be < 2 X ULN (within 2 weeks prior to registration)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 X institutional ULN (within 2 weeks prior to registration)
• Albumin >= 3.0 g/dL (within 2 weeks prior to registration)
• Women must not be pregnant or breast-feeding because the study treatment administered may cause harm to an unborn fetus or breastfeeding child. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must be strongly advised to use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for at least 6 months after the completion of treatment

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patient must have histologically confirmed HER2-positive primary invasive breast carcinoma, determined by local testing. The tumor must have either HER2 IHC result of 3+ or HER2/CEP17 ratio > 2 with > 4.0 HER2 signals per cell by ISH. Tumors with HER2/CEP17 ISH ratio < 2 are ineligible, even if HER2 copy number is > 6, unless HER2 IHC result is 3+.
• Patients hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) status must be known and will be determined by local testing. Patients with either hormone receptor -positive or hormone receptor- negative HER2-positive breast cancer are eligible
• Patients must have AJCC 8th Edition stage II or IIIa according to anatomic staging table at diagnosis
• Patients without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-3)
• Patients with nodal involvement (cN1-2) are eligible if T1-3
• Patients with clinical T4 or N3 disease are not eligible
• Patient must be willing and able (i.e., have no contraindication) to receive standard adjuvant therapy, consisting of HER2-directed therapy, radiation (if indicated) and endocrine therapy (if ER+) if achieving pCR at surgery
• Patient with bilateral invasive breast cancers are eligible if both cancers are HER2-positive (as defined in 3.1.3) at least one meets protocol eligibility and neither cancer renders the patient ineligible (i.e. per eligibility 3.1.5)
• Patients with multiple ipsilateral invasive tumors are eligible as long as all tumors are HER2-positive, and at least one tumor focus meets eligibility criteria (per eligibility 3.1.5). Multiple lesions that appear part of the same index tumor do not require additional biopsy/HER2 testing. Multiple lesions that appear part of the same index tumor do not require additional biopsy/HER2 testing. However, even if biopsy is not deemed necessary, consideration should be given to placing a clip in any lesion that is 1 cm or further from the primary tumor to ensure that all tumor is removed at surgery AND that the pathologist can locate all primary sites of tumor to assess pathologic response at surgery.
• Patients with a history of other non-breast malignancies are eligible if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
• Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, and localized papillary or follicular thyroid cancer who have completed recommended treatment including surgery. Patients with any other cancers within the last 5 years are ineligible.
• Patents must have a left ventricular ejection fraction (LVEF) within normal institutional parameters (or > 50%)
• Patients must not have > grade 1 peripheral neuropathy of any etiology.
• Patients must have a bilateral mammogram and a diagnostic breast ultrasound [on the side of the cancer(s)] (with or without breast MRI) performed at screening. An axillary ultrasound on the side of the cancer(s) is also required. However, if a patient has a negative axillary physical exam and a baseline MRI without suspicious lymph nodes performed before axillary ultrasound, axillary ultrasound may be omitted. Comprehensive breast and axillary imaging must be performed within 42 days of registration (i.e. the patient's mammogram/ breast ultrasound /axillary ultrasound OR their breast MRI).
• Baseline imaging of the ipsilateral axilla by ultrasound or breast MRI is mandatory. For subjects with axillary lymph node(s) suspicious on clinical exam or imaging, patient must be willing to have a needle aspiration or core biopsy to determine the presence of metastatic disease in the lymph nodes. A clip must be placed in the involved axillary lymph node. (If there are more than 1 suspicious axillary nodes, only one clipped node is required).
• Patient of childbearing potential and sexually active patients must use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 7 months after the last dose of study treatment.
• Patient must be willing and able to sign informed consent
• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to protocol registration)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to protocol registration)
• Platelets >= 100,000/mcL (obtained =< 28 days prior to protocol registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained =< 28 days prior to protocol registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 28 days prior to protocol registration)
• Creatinine =< 1.5 x institutional ULN (obtained =< 28 days prior to protocol registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• 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
• Patients must not have impaired decision-making capacity
• Patient must not have a history of any prior (ipsilateral or contralateral) invasive breast cancer
• One exception: a patient with a history of T1N0 triple negative breast cancer diagnosed more than 10 years earlier, who remains disease free is eligible
• Patient must not have prior ipsilateral ductal breast carcinoma in situ (DCIS). Patients with prior lobular breast carcinoma in situ (LCIS), atypical hyperplasia, other high risk benign lesions or contralateral DCIS (without evidence of microinvasion) are eligible
• NOTE: Patients currently receiving endocrine therapy for prior contralateral DCIS are eligible
• Patient must not have stage IV (metastatic) breast cancer
• Staging studies (computed tomography [CT] chest/abdomen/pelvis and a bone scan or positron emission tomography [PET]-CT scan) are required for stage III disease or those with abnormal baseline liver function tests (LFTs), symptoms (e.g. new bone pain) or abnormal physical exam findings (National Comprehensive Cancer Network [NCCN] guidelines version [V]1.2019)
• Patient must not have T4 and/or N3 disease, including inflammatory breast cancer
• Patient must not have any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation or experimental therapy
• Patients must not have > grade 1 peripheral neuropathy of any etiology
• Patient must not have a concurrent serious medical condition that would preclude completion of study therapy. For example, uncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to registration, unstable angina, congestive heart failure (CHF) or serious cardiac arrhythmia requiring medication and other concurrent serious diseases that may interfere with planned treatment
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive from the time of registration, while on study treatment, and until at least 7 months after the last dose of study treatment. All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
• All patients of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• Patient must have AML with an IDH2 mutation identified from a peripheral blood or bone marrow sample at the time of diagnosis and/or relapsed/refractory disease
• Patient must have bone marrow assessment (aspiration or biopsy) with > 5% leukemic blasts by morphology and/or flow cytometry in at least one of the following clinical scenarios:
• Second or greater relapse after chemotherapy or hematopoietic stem cell transplant (HSCT)
• Refractory after >= 2 attempts at induction therapy
• Relapsed patients
• Must not have received prior re-induction therapy for this relapse
• Each block of chemotherapy (i.e., cytarabine, daunorubicin and etoposide [ADE], cytarabine and mitoxantrone [MA]) is a separate re-induction attempt
• Donor lymphocyte infusion (DLI) is considered a re-induction attempt
• Refractory patients
• Each attempt at induction therapy may include up to two chemotherapy courses
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Evaluation of cerebrospinal fluid (CSF) is only required if there is a clinical suspicion of central nervous system (CNS) involvement by leukemia during eligibility screening. Should a patient be found to have CNS2 or CNS3 status by CSF prior to eligibility screening, patient may receive intrathecal chemotherapy > 72 hours prior to starting study drug. CNS1 status must be established before starting study drug
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• >= 14 days must have elapsed after the completion of other cytotoxic therapy with the exception of hydroxyurea. Additionally, patients must have fully recovered from all acute toxic effects of prior therapy. NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy
• Intrathecal chemotherapy must be completed >= 72 hours prior to the start of the first cycle of treatment
• Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell Infusions (with or without total body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including DLI or boost infusion:
• >= 60 days after infusion for bone marrow or stem cell transplant and
• >= 4 weeks after infusion for any stem cell infusion including DLI or boost infusion
• There must be no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular Therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• XRT/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
• Study-specific limitations on prior therapy: small molecule investigational agents: >= 14 days or > 5 half-lives must have elapsed from the last dose of the agent, whichever is greater
• Platelet count >= 20,000/mm^3 (may receive platelet transfusions). These patients must not be known to be refractory to red cell or platelet transfusion
• Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
• Creatinine clearance or radioisotope glomerular filtration rate [GFR] >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: Maximum serum creatinine (mg/dL)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male); 1.4 (female
• >= 16 years: 1.7 (male); 1.4 (female)
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 225 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• Serum albumin >= 2 g/dL
• Left ventricular ejection fraction of >= 50% by echocardiogram
• Regulatory Requirements
• All patients and/or their parents or legal authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
• AML associated with Down syndrome or t(15;17) is not eligible for study
• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy and for 4 months after the last dose of enasidenib. Abstinence is an acceptable method of birth control. It is not known if enasidenib is present in breast milk. Breastfeeding is not recommended during therapy or for at least 30 days after the last dose of enasidenib
• Concomitant Medications:
• Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid. The use of corticosteroids to manage the side effect of IDH inhibitor-associated differentiation syndrome (IDH-DS), is permitted on study
• Investigational drugs: Patients who are currently receiving another investigational drug are not eligible
• Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible (except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy; the use of hydroxyurea to manage the side effect of IDH-DS, is permitted on study)
• Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients must be able to swallow intact tablets whole.
• Patients with known hypersensitivity to any of the components of enasidenib are not eligible.
• Patients with prior exposure to enasidenib or another IDH2 inhibitor are not eligible.
• Patients taking the following drugs will be excluded from study entry unless these drugs are discontinued or patients are transferred to a medically acceptable alternative > 5 half-lives before the first dose of enasidenib.
• Drugs with a narrow therapeutic range that are sensitive substrates of the following cytochrome P450 (CYP) enzymes: CYP2C8 (e.g. paclitaxel), 2C9 (e.g. phenytoin and warfarin), 2C19 (e.g. s-mephenytoin), 2D6 (e.g. thioridazine), and 1A2 (e.g. theophylline and tizanidine).
• Breast cancer resistant protein (BCRP) transporter-sensitive substrate rosuvastatin
• Patients with the following leukemia complications are not eligible for this trial:
• No intrathecal chemotherapy is permitted on study. Prior to study enrollment, cerebrospinal fluid (CSF) evaluation is only required if there is a clinical suspicion for CNS leukemia. Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome) are not eligible for this trial
• Immediately life-threatening, severe complications of leukemia including uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
• Infection: Patients who have an uncontrolled infection or patients with known human immunodeficiency virus (HIV) or active hepatitis B or C are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

• Previously registered to A151216 (NCT02194738)
• Central and/or local testing of EGFR with no EGFR exon 19 deletion or EGFR L858 R mutation (applicable to non-squamous patients only)
• Central and/or local testing of ALK with no ALK rearrangement (failed testing is considered negative) (applicable to non-squamous patients only)
• Central and/or local testing of PD-L1 immunohistochemistry (IHC) using one of the following assays: DAKO 22C3, DAKO 28-8, EIL3N or SP263
• Note: Local testing results of EGFR and ALK by a local Clinical Laboratory Improvement Act (CLIA) certified laboratory is acceptable. The report must indicate the result as well as the CLIA number of the laboratory that performed the assay. Local result of PD-L1 by DAKO 22C3, Dako 28-8, EIL3N or SP263 are acceptable for enrollment on A081801. Patients with local results for EGFR, ALK and PD-L1 still need to be registered to A151216 and follow all the submissions requirements but do NOT need to wait for the results to proceed to A081801 registration
• Completely resected stage IIA, IIB IIIA or IIIB (T3-4N2) non-small cell lung cancer (NSCLC) (squamous or non-squamous) with negative margins (complete R0 resection). Patients will be staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual, 2017
• Note: Patients with pathologic N2 disease, completely resected, are eligible. However, patients known to have N2 disease prior to surgery are not eligible; guidelines do not recommend up-front surgery for this population
• Complete recovery from surgery. Registration to A081801 must be 30-77 days following surgery
• No prior neoadjuvant or adjuvant therapy for current lung cancer diagnosis
• No prior allogeneic tissue/solid organ transplant
• No current pneumonitis or history of (non-infectious) pneumonitis that required steroids
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0-1
• No active auto-immune disease that has required systemic treatment within the last 2 years (e.g., disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid release therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• No patients with a "currently active" second malignancy that is progressing or has required active treatment within the last 3 years. Participants with non-melanoma skin cancers or carcinoma in situ (e.g., breast carcinoma or cervical cancer in situ) that have undergone potentially curative therapy are eligible
• No hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• No live vaccine within 30 days prior to registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• No known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 8 gm/dl
• Calculated (Calc.) creatinine clearance >= 45 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, uncontrolled cardiac arrhythmia, unstable angina pectoris, that would limit compliance with study requirements

• Patients with pathologically confirmed myeloma.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2.
• For cross-sectional study, no additional required treatment schedule. For longitudinal study: Patients scheduled to undergo bone marrow biopsy (BMB) and induction therapy (or have gone through 1-2 cycles of induction therapy), followed by either bone marrow transplantation (BMT) or consolidation therapy.
• Women of child-bearing potential must agree to undergo a urine pregnancy screening to prevent imaging of pregnant patients. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 1) Has not undergone a hysterectomy or bilateral oophorectomy; or 2) Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Ability to understand and the willingness to sign a written informed consent.
• Subjects may not be receiving any other investigational agents for the treatment of the cancer under study.
• 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, in the opinion of the investigator, would limit compliance with study requirements.
• Subjects must not be pregnant or nursing; since pregnancy is a contraindication to administration of gadolinium-based contrast agents. Furthermore, there is a potential for congenital abnormalities and the potential to harm nursing infants, associated with FDG-PET.
• Any contraindication to MRI per Radiology Department's routine protocol, e.g. MRI-incompatible objects, including but not limited to medical devices and other foreign bodies.
• Known severe allergic reaction to Gadolinium-based contrast agents.
• Patients with uncontrollable claustrophobia, severe lower back pain, and uncontrollable tremors, to the point that it would render them unable to tolerate an MRI study.

1. Age: Patients must be less than 22 years at the time of enrollment; there is no lower age limit. 2. All participants must have an identified pathogenetic constitutional NF1 mutation OR the clinical diagnosis of NF1 using the NIH Consensus Conference criteria. 3. Diagnosis: LGG (WHO Grade 1 and 2) of the brain and spinal cord are eligible. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings. Biopsy for histologic diagnosis is required if there is clinical suspicion for a high-grade tumor; special attention is recommended in older adolescents or young adults to the potential for malignant transformation. Patients with metastatic disease are eligible. 4. Patients must meet at least one of the following criteria for progression or recurrence of a previously treated target tumor: 1. Progression or recurrence on MRI. 2. New or worsening neurologic symptoms attributable to the target tumor. 3. For patients with OPG: visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year by examination or history, attributable to tumor. 5. Measurable Disease: Patients must have two-dimensional measurable tumor >1cm2. 6. Prior Therapy: Patients must have had at least one prior medical treatment for the target LGG. 7. Performance Level: Patients must have a performance status of equal or > than 50 using Karnofsky for patients equal or ≥ 16 years of age and Lansky for patients < 16 years of age. 8. Patients must have recovered to grade ≤1 from any acute toxicities from all prior treatments. to enroll on this study and meet time restrictions from end of prior therapy as defined below: 1. Myelosuppressive chemotherapy: must have received the last dose of myelosuppressive therapy at least 4 weeks prior to study registration, or at least 6 weeks if nitrosourea. 2. Investigational/biological agent: Patient must have received the last dose of other investigational, immunotherapy, or biological agent > 14 days prior to study registration or at least 5 half-lives, whichever is greater. Bevacizumab last dose > 36 days prior to enrollment. 3. Radiation therapy: Patients SHOULD NOT have received prior irradiation. 4. Study specific limitations on prior therapy: There is no limit on the number of prior treatment regimens. 5. Growth factor(s): Must not have received any hematopoietic growth factors within 7 days of study entry or > 14 days if pegylated GCSF is used. 6. Prior surgery: At the time of enrollment, must be ≥ 3 weeks from prior major surgery such as craniotomy, orthopedic surgery, abdominal surgery or ≥1 week from minor surgery and completely recovered. Port or central line placement is not considered a major surgery. 9. Organ Function Requirements: All patients must have adequate organ function defined as: 9.1 Hematologic Function: 1. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs) 2. ANC: > 750/mm3. Must be at least 7 days after last dose of growth factor or > 14 days since last dose of pegylated GCSF 3. Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last transfusion) 9.2 Renal Function: Serum creatinine which is less than 1.5 times ULN for age (as per the table below) or GFR > 70 ml/min/1.73m2 Renal Function Normal for Age Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 ≥ 16 years 1.7 1.4 Liver Function: 1. Total bilirubin < 1.5 x ULN (Children with diagnosis of Gilbert's Syndrome will be allowed on the study regardless of their total and indirect bilirubin levels as long as the direct bilirubin is less than 3.1 mg/dL.) 2. SGPT (ALT) ≤ 5 x ULN 3. SGOT (AST) ≤ 5 x ULN Pulmonary Function: No evidence of dyspnea at rest, and a pulse oximetry ≥ 92%. Reproductive Function: Female patients of childbearing potential must have negative serum or urine pregnancy test within 7 days prior to the first dose of poly-ICLC. Patient must not be pregnant or breast-feeding. Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, including abstinence, while being treated on this study and for 90 days following cessation of treatment. 10. Patient is able to start treatment within 7 days after enrollment. 11. Patients with neurological deficits must be stable for a minimum of 1 week prior to enrollment. 12. Patients are only eligible if complete resection of the LGG with acceptable morbidity is not feasible, or if a patient with a surgical option refuses surgery. 13. Parents/legal guardians must provide written informed consent and agree that they will comply with the study. 1. Prior radiation treatment for the low-grade glioma. 2. Prior exposure to poly-ICLC. 3. Patients currently receiving other anti-tumor therapy or experimental therapy (targeted agents, chemotherapy radiation). 4. Patients with a current or prior diagnosis of malignant glioma (WHO grade III or IV). 5. Patients with a prior diagnosis of malignant peripheral nerve sheath tumor or other malignancy requiring treatment in the last 48 months. 6. Patients may not have fever (≥38.50 C) within 3 days of enrollment. 7. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study. 8. Active auto-immune illness. 9. Pregnant or lactating females. 10. Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 90 days after stopping study therapy are not eligible. 11. Severe unresolved infection that requires systemic IV antibiotics. 12. Patients with any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy. 13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, impaired gastrointestinal function, or psychiatric illness/social situations that would limit compliance with study requirements. 14. Patients requiring high doses of steroids. Patients may not be on immunosuppressive therapy, including corticosteroids (with the exception of physiologic replacement, defined as ≤ 0.75 mg/m2/day dexamethasone or equivalent) at time of enrollment. However, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study.

• Diagnosis of primary progressive multiple sclerosis (PPMS).
• Expanded disability status scale (EDSS) score at screening and baseline, from 3 to 6.5 inclusive.
• Average T25FWT score over two trials at screening and over two trials at baseline respectively, up to 150 (inclusive) seconds
• Average 9HPT score over four trials (two trials with each hand) at screening and over four trials (two trials with each hand) at baseline respectively, up to 250 (inclusive) seconds
• Score of >/= to 2.0 on the Functional Systems scale for the pyramidal system that was due to lower extremity findings at screening and baseline.
• Documented MRI of brain with abnormalities consistent with MS
• Participants requiring symptomatic treatment for MS and/or physiotherapy must be treated at a stable dose. No initiation of symptomatic treatment for MS or physiotherapy within 4 weeks of randomization.
• Participants must be neurologically stable for at least 30 days prior to randomization and baseline.
• Disease duration from the onset of MS symptoms; if EDSS score at screening is less or equal to 5, disease duration must be less than 10 years; If EDSS score at screening is more than 5, disease duration must be less than 15 years
• Documented evidence of the presence of at least one cerebrospinal fluid-specific oligoclonal bands.
• For females of childbearing potential, agreement to remain abstinent or use adequate contraceptive methods.
• For female participants without reproductive potential, may be enrolled if post-menopausal unless receiving a hormonal therapy for her menopause or if surgically sterile.
• History of relapsing remitting or secondary progressive MS at screening.
• Any known or suspected active infection at screening or baseline (except nailbed infections), or any major episode of infection requiring hospitalization or treatment with IV antimicrobials within 8 weeks or treatment with oral antimicrobials within 2 weeks, prior to and during screening.
• History of confirmed or suspected progressive multifocal leukoencephalopathy.
• History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening.
• Immunocompromised state.
• Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization.
• Inability to complete an MRI or contraindication to gadolinium administration.
• Contraindications to mandatory pre-medications for IRRs.
• Known presence of other neurologic disorders that could interfere with the diagnosis of MS or assessments of efficacy and/or safety during the study.
• Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study.
• Significant, uncontrolled disease that may preclude participant from participating in the study.
• History of or currently active primary or secondary, non-drug-related, immunodeficiency.
• Pregnant or breastfeeding or intending to become pregnant.
• Lack of peripheral venous access.
• History of alcohol or other drug abuse within 12 months prior to screening.
• Treatment with any investigational agent or treatment with any experimental procedure for MS.
• Previous use of anti-CD20s (including ocrelizumab), unless the last infusion was more than 2 years before screening, B-cell count is normal, and the stop of the treatment was not motivated by safety reasons or lack of efficacy.
• Any previous treatment with mitoxantrone, cladribine, atacicept, alemtuzumab, and daclizumab
• Previous treatment with fingolimod, siponimod, or ozanimod within 6 weeks of baseline
• Previous treatment with natalizumab within 4.5 months of baseline
• Previous treatment with interferons beta (1a or 1b), or glatiramer acetate within 2 weeks of baseline
• Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label. If the washout requirements are not described in the applicable local label, then the wash out period must be five times the half-life of the medication.
• Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation.
• Any previous history of transplantation or anti-rejection therapy.
• Treatment with intravenous (IV) immunoglobulin (Ig) or plasmapheresis within 12 weeks prior to randomization.
• Systemic corticosteroid therapy within 4 weeks prior to screening.
• Positive screening tests for active, latent, or inadequately treated hepatitis B
• Sensitivity or intolerance to any ingredient (including excipients) of ocrelizumab.
• Any additional exclusionary criterion as per ocrelizumab local label, if more stringent than the above.

1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours 2. Age ≥18 years old 3. Able to provide informed consent, or (as allowed by IRB), immediate availability of designated legally authorized representative to provide consent by proxy 4. Anticipated hospitalization for >48 hours 1. Participation in any other clinical trial with antiviral activity against COVID-19 2. Breastfeeding women 3. Known hypersensitivity to atovaquone or formulation excipient 4. Active treatment with rifampin 5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma gondii 6. Not expected to survive for 72 hours. 7) >14 days from symptom onset