• Inborn and outborn preterm infants
• 23 0/7-28 6/7 weeks gestation
• ≤24 hours postnatal age
• Hematocrit > 60%
• Infants with known congenital or chromosomal anomalies, including congenital heart disease and known brain anomalies
• Hemorrhagic or hemolytic disease
• EEG- confirmed seizures
• Congenital thrombotic disease
• Systolic blood pressures >100 mm Hg while not on pressor support
• Receiving Epo or Darbe clinically, or planning to receive Epo or Darbe during hospitalization
• Infants in whom no aggressive therapy is planned
• Family will NOT be available for follow-up at 22-26 months

• Feasibility Phase: Patients must be < 21 years of age at the time of enrollment; please note: the feasibility phase is complete, effective with amendment #1
• Efficacy Phase: Patients must be =< 40 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification, are eligible to enroll on the study based upon stage, group, and age, as below
• RMS types included under embryonal rhabdomyosarcoma (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2013 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant); classification of alveolar rhabdomyosarcoma (ARMS) in the 2013 WHO classification is the same as in the ICR and includes classic and solid variants
• ERMS
• Stage 1, group III (non-orbit)
• Stage 3, group I/II
• Stage 2/3, group III
• Stage 4, group IV, < 10 years old
• ARMS:
• Stages 1-3, groups I-III
• Specimen Submission: Patients must have sufficient tissue available for the required biology study
• Lansky performance status score >= 50 for patients =< 16 years of age; Karnofsky performance status score >= 50 for patients > 16 years of age
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 75,000/uL
• 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:
• 1 month to < 6 months old: 0.4 mg/dl (male), 0.4 mg/dl (female)
• 6 months to < 1 year old: 0.5 mg/dl (male), 0.5 mg/dl (female)
• 1 to < 2 years old: 0.6 mg/dl (male), 0.6 mg/dl (female)
• 2 to < 6 years old: 0.8 mg/dl (male), 0.8 mg/dl (female)
• 6 to < 10 years old: 1 mg/dl (male), 1 mg/dl (female)
• 10 to < 13 years old: 1.2 mg/dl (male), 1.2 mg/dl (female)
• 13 to < 16 years old: 1.5 mg/dl (male), 1.4 mg/dl (female)
• >= 16 years old: 1.7 mg/dl (male), 1.4 mg/dl (female)
• Patients with an elevated serum creatinine due to obstructive hydronephrosis secondary to tumor are still eligible; however, patients with urinary tract obstruction by tumor must have unimpeded urinary flow established via diversion (i.e. percutaneous nephrostomies or ureteric stents) of the urinary tract
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• 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 who have previously received temsirolimus, another mTOR inhibitor, or any other investigational agent
• Patients who have received any chemotherapy (excluding steroids) and/or RT prior to this enrollment
• Patients with uncontrolled hyperglycemia
• Patients with uncontrolled hyperlipidemia
• 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 at least 3 months after treatment is completed
• Female patients who are pregnant are not eligible; Note: a pregnancy test is required for female patients of childbearing potential prior to study entry
• Lactating females who plan to breastfeed their infants are not eligible

Key Inclusion Criteria
• Patients ≥6 months and up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk
• Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN2
• Negative gene testing for SMN2 gene modifier mutation (c.859G>C)
• Onset of clinical signs and symptoms consistent with spinal muscular atrophy (SMA) at < 12 months of age
• Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds. Child should not use arms or hands to balance body or support position (Wijnhoven 2004)
• Be up-to-date on childhood vaccines. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics (AAP 2009) Key Exclusion Criteria
• Current or historical ability to stand or walk independently
• Contraindications for spinal tap procedure or administration of intrathecal therapy or presence of an implanted shunt for the drainage of CSF or an implanted central venous (CNS) catheter
• Severe contractures as determined by designated Physical Therapist(s) at screening that interfere with either the ability to attain/demonstrate functional measures or interferes with ability to receive intrathecal (IT) dosing
• Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination
• Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose administration
• Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening while the patient is awake, or for high altitudes > 1000 m, oxygen saturation < 92% while the patient is awake
• Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and highest value on day of dosing
• Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
• Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
• Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
• Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
• Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for hepatitis B or C, or Zika virus)
• Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within two (2) weeks prior to study entry
• Respiratory infection requiring medical attention, medical intervention or increase in supportive care of any manner within four (4) weeks prior to study entry
• Severe non-pulmonary/respiratory tract infection within four (4) weeks before study dosing or concomitant illness that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer such as:
• Major renal or hepatic impairment
• Known seizure disorder
• Diabetes mellitus
• Idiopathic hypocalciuria
• Symptomatic cardiomyopathy
• History of bacterial meningitis or brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computerized tomography (CT) that would interfere with the lumbar puncture (LP) procedures or CSF circulation
• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
• Known allergy or hypersensitivity to iodine or iodine-containing products
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy within 3 months of study dosing
• Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose administration
• Anti-AAV9 antibody titers >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay
• Should a potential patient demonstrate anti AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the anti AAV9 antibody titer upon retesting is ≤ 1:50
• Abnormal laboratory values considered to be clinically significant (INR >1.4), GGT >3XULN, Bilirubin ≥3.0 mg/dL, Creatinine ≥1.0 mg/dL, Hgb <8 or >18 g/Dl; WBC >20,000 per cmm) prior to study dosing
• Participation in recent SMA treatment clinical trial or receipt of an investigational or approved compound product or therapy received with the intent to treat SMA at any time prior to screening for this study
• Oral beta agonists must be discontinued 30 days prior to dosing.
• Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study
• Expectation of major surgical procedures during the 1-year study assessment period

• Completed study drug treatment in a parent study; or had study drug interruption(s) in a parent study but completed study visits up to the last scheduled visit of the Treatment Period in the parent study.
• History of drug intolerance in a parent study that would pose an additional risk to the subject in the opinion of the investigator.
• Current participation in an investigational drug trial (other than a parent study) Other protocol defined Inclusion/Exclusion criteria may apply.

Each patient must meet the following criteria to be enrolled in this study. 1. Is a child or an adolescent of 10 to <18 years old, at Visit 1 (Screening) 2. Has been diagnosed with type 2 diabetes mellitus per American Diabetes Association diagnostic criteria 3. HbA1c of 6.5% to 11.0%, inclusive, in patients not taking insulin/SU, and of 6.5% to 12.0%, inclusive, in patients taking insulin/SU, at Visit 1 (Screening) 4. Has a C-peptide of >0.6 ng/L at Visit 1 (Screening) 5. Has been treated with diet and exercise alone or in combination with a stable dose of an oral antidiabetic agent (e.g., metformin and/or SU) and/or insulin for their type 2 diabetes for at least 2 months prior to Visit 1 (Screening) 6. Has a fasting plasma glucose concentration <280 mg/dL (15.5 mmol/L) at Visit 1 (Screening) Patients who meet any of the following criteria will be excluded from the study. 1. Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the Investigator, including but not limited to the following conditions: 1. Hepatic disease (defined by aspartate or alanine transaminase >3.0 times the upper limit of normal (ULN) 2. Renal disease or serum creatinine >1.5 mg/dL (132.6 µmol/L) (males) or 1.4 mg/dL (123.8 µmol/L) (females) 3. Gastrointestinal disease deemed significant by the Investigator 4. Organ transplantation 5. Chronic infection (e.g., tuberculosis, human immunodeficiency virus, hepatitis B virus, or hepatitis C virus) 6. Clinically significant malignant disease (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 1 (Screening) 2. Has positive antibody titers to glutamic acid decarboxylase (GAD65) or islet cell antigen (ICA512) at Visit 1 (Screening) 3. Has a personal or family history of elevated calcitonin, calcitonin >100 ng/L, medullary thyroid carcinoma, or multiple endocrine neoplasia-2 4. Has ever used exenatide (exenatide once weekly [exenatide LAR], exenatide BID, BYETTA, or any other formulation) or any glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., liraglutide [Victoza®]) 5. Is pregnant

• Age 13-18 years old
• Diagnosed with Type 1 Diabetes Mellitus >1 year ago with at least one positive diabetes autoantibody
• Patient on multiple daily injections of insulin, with no change to insulin type within the past 3 months
• ≥2 separate HbA1c values (at least 60 days apart) ≥10.0% in the past year, with the most recent HbA1c value ≥10.0%
• English-Speaking (patient and at least 1 parent)
• Patient or parents must own a smart phone or other device compatible with Glooko
• Patients on Continuous Subcutaneous Insulin Infusion
• Diagnosed with Type 2 Diabetes or taking metformin
• Other chronic medical condition that would be likely to affect blood glucose. Exceptions include:
• Hypothyroidism on treatment with normal thyroid function tests
• Asthma with no oral steroids within past 3 months
• Unstable social situation that could compromise diabetes management or study follow-up in the judgment of the investigators

• Eligible subjects will be as follows: 1. 4 weeks to 17 years of age, 2. fulfill the American Heart Association case definition for complete or incomplete KD, 3. have had fever (T ≥38°C) for 3 to 10 days prior to initial IVIG treatment, 4. have fever (T ≥38°C orally or rectally) between 36 hours and 7 days after end of the first IVIG infusion without other likely cause 1. Patient treated with infliximab or steroids for present illness (pts who received oral steroids as outpatients prior to KD diagnosis but who otherwise qualify for the study will not be excluded) 2. Known prior infection with tuberculosis, coccidiomycosis, or histoplasmosis.

Key
• Advanced solid tumor for which, in the opinion of the Investigator, no other standard therapy offers greater benefit.
• A solid tumor diagnosis in the setting of: 1. a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor 2. a documented NTRK fusion unresponsive to a prior TRK inhibitor 3. a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor
• NTRK gene fusions will be identified via a CLIA certified (or equivalent) laboratory. Exception: Patients with Infantile Fibrosarcoma (IFS) and congenital mesoblastic nephroma (CMN) may be enrolled based on ETV6+ FISH test without identifying NTRK3
• Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3 (age ≥16) or Lansky Performance Score (LPS) ≥40% (age<16). If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Status (KPS) (age ≥16) or LPS (age<16) ≥ 50%
• Life expectancy > 4 weeks
• Adequate hematologic, hepatic and renal function.
• Patients with stable CNS primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms and steroid use (if applicable) have been stable for 7 days prior to the first dose of LOXO-195
• Ability to receive study drug orally or by enteral administration Key
• Required treatment with certain strong CYP3A4 inhibitors or inducers.
• Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of LOXO-195 or prolongation of the QT interval corrected (QTcF) > 480 msec within the past 6 months
• Major surgery within 7 days of enrollment
• Uncontrolled systemic bacterial, fungal or viral infection
• Pregnancy or lactation.
• Known hypersensitivity to any of the components of LOXO-195 or Ora-Sweet® SF and OraOlus, for patients receiving liquid suspension

• 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 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
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted below; note that rapid central pathology review is required in some cases; please note: all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by immunohistochemistry (IHC) according to the practices at the institution
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining
• In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy
• Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:
• Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.)
• Uncorrectable coagulopathy
• For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:
• The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment
• Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment
• Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims
• Patients may have had surgical resection of the hepatic malignancy prior to enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
• 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)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 06 (male and female)
• 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)
• Total bilirubin =< 5 x upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 10x upper limit of normal (ULN) for age
• Shortening fraction of >= 27% by echocardiogram (for patients on doxorubicin-containing regimens [Groups C, D, E, and F]), or
• Ejection fraction of >= 50% by radionuclide angiogram (for patients on doxorubicin-containing regimens (Groups C, D, E, and F)
• Normal pulmonary function tests (including diffusion capacity of the lung for carbon monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen); for patients who do not have respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
• 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
• Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• Patients who previously received a solid organ transplant
• This criteria apply ONLY to patients who will receive chemotherapy (all groups other than Group E1):
• Female patients who are pregnant; 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
• Note for Group F: patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment

1. ≥ 12 years of age at the time Informed Consent/ Assent is signed. 2. Weight ≥ 40 kg. 3. FEV1 ≥ 40% predicted and < 100% predicted in the last 12 months. 4. Physician-initiated treatment with an IV antibiotic 2 or 3 times in the last 12 months for a new PEx or physician-initiated treatment with an IV antibiotic 1 time in the last 12 months plus physician-initiated treatment with oral antibiotic(s) 1 or more times in the past 12 months for a new PEX. 1. Severe or unstable CF at screening or Visit 1. 2. Any of the following values for laboratory tests at screening: 1. A positive pregnancy test. 2. Hemoglobin < 10 g/dL in males and < 9 g/dL in females. 3. Neutrophils < 1.0 x 10^9 /L. 4. Platelets < 75 x 10^9/L. 5. Creatinine clearance < 50 mL/min according to Modification of Diet in Renal Disease (MDRD) Study equation. 6. Serum transaminases > 2.5 x upper limit of normal. 3. Any medical condition or concurrent medical therapies at screening or Visit 1 that may put the subject at greater safety risk, influence response to study drug or interfere with study assessments.

Eligibility criteria: Infants are eligible if they meet all of the following criteria:
• ≥ 36 0/7 weeks PMA by best obstetric estimate AND birth weight of ≥ 2000g
• postnatal age ≤7 days (168 hours of age)
• invasive mechanical ventilation (defined as ventilation with an endotracheal tube) and
• one arterial blood gas with an OI ≥ 10 (after tracheal tube obstruction and other easily resolvable mechanical causes for increased OI are ruled out) on the most recent arterial blood gas within 12 hours prior to the time of randomization.
• if an arterial blood gas is not available at the time of randomization, a preductal OSI of ≥ 5 can be used as an inclusion criterion instead of OI ≥ 10; (the OSI should be based on the most recent preductal pulse oximetry recording and must be within 12 hours of randomization)
• postnatal blood gas with PCO2 ≤ 80 mmHg (arterial, capillary or venous blood gas) on the most recent blood gas sample obtained within 12 hours prior to randomization Note: Criteria (iv) to (vi) must be met at the most recent analysis within 12 hours prior to randomization. Infants are ineligible if they meet any of the following criteria:
• known hypertrophic cardiomyopathy
• Note 1: infants of diabetic mothers with asymmetric septal hypertrophy can be included as long as there is no evidence of obstruction to left ventricular outflow tract on echocardiogram,
• Note 2: infants with other acyanotic congenital heart disease (CHD) and CDH may be included in the study and will be a predetermined subgroup for analysis)
• cyanotic CHD
•transposition of great arteries (TGA), total anomalous pulmonary venous return (TAPVR), partial anomalous pulmonary venous return (PAPVR), truncus arteriosus (TA), tetralogy of Fallot (TOF), single ventricle physiology
•hypoplastic left heart syndrome (HLHS), tricuspid atresia, critical pulmonic stenosis or atresia etc.,
• enrolled in conflicting clinical trials (such as a randomized controlled blinded trial of another pulmonary vasodilator therapy); Note: mothers enrolled in fetal tracheal occlusion studies such as FETO may be enrolled if permitted by investigators of the fetal tracheal occlusion study; [FETO refers to fetoscopic endoluminal tracheal occlusion and involves occlusion of fetal trachea with a balloon device at mid-gestation and subsequent removal in later gestation]
• infants with bilateral CDH o Note 3: infants with anterior and central defects are included in the study
• associated abnormalities of the trachea or esophagus (trachea-esophageal fistula, esophageal atresia, laryngeal web, tracheal agenesis)
• renal dysfunction (with serum creatinine > 2 mg/dL not due to maternal factors) or severe oligohydramnios associated with renal dysfunction at randomization; renal dysfunction may be secondary to renal anomalies or medical conditions such as acute tubular necrosis
• severe systemic hypotension (mean blood pressure < 35 mm Hg for at least 2 h with a vasoactive inotrope score of > 30)
• decision is made to provide comfort/ palliative care and not full treatment
• Intracranial bleed (including the following findings on the cranial ultrasound)
• Cerebral parenchymal hemorrhage
• Blood/echodensity in the ventricle with distension of the ventricle
• Periventricular hemorrhagic infarction
• Posterior fossa hemorrhage
• Cerebellar hemorrhage
• persistent thrombocytopenia (platelet count < 80,000/mm3) despite blood product administration on the most recent blood draw prior to randomization
• coagulopathy (PT INR > 1.7) despite blood product administration on the most recent blood draw (if checked
•there is no reason to check PT for the purpose of this study)
• aneuploidy associated with short life span (such as trisomy 13 or 18) will not be included in the study (infants with trisomy 21 can be included in the study)
• elevated arterial, venous or capillary PCO2 > 80 mmHg in spite of maximal ventilator support (including high frequency ventilation) on the most recent blood gas obtained within 12 hours prior to randomization
• use of milrinone infusion prior to randomization (the use of other inhaled pulmonary vasodilators such as iNO, inhaled epoprosternol, inhaled PGE1 and oral such as endothelin receptor antagonists is permitted
•Note: it is unlikely to be on oral pulmonary vasodilators early in the course of CDH)
• ongoing therapy with parenteral (intravenous or subcutaneous) pulmonary vasodilators such as IV/SQ prostacyclin analogs (Epoprostenol
•Flolan or Treprostinil
•Remodulin or PGE1
•Alprostadil) or IV phosphodiesterase 5 inhibitors (sildenafil
•Revatio) at the time of randomization. In addition, initiation of therapy with these two classes of parenteral medications during the first 24 hours of study drug initiation is not permitted and will be considered a protocol deviation. The risk of systemic hypotension is high during the first 24 hours of study-drug (milrinone) infusion and hence parenteral administration of other pulmonary vasodilators is avoided to minimize risk of hypotension.
• Subjects already on ECMO or patients who are being actively considered for ECMO by the neonatal or surgical team
• attending (neonatal, critical care or surgical) refusal for participation in the trial (including concern about presence of hemodynamic instability)

Inclusion Criteria Age -Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment. Diagnosis
• Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or mixed phenotypic acute leukemia with ≥ 5% blasts in the bone marrow (M2 or M3), with or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma.
• Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of detectable disease (minimal residual disease level acceptable) with or without extramedullary disease Performance Level -Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. Prior Therapy
• Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, unless otherwise specified. Subjects with disease related cytopenias will be eligible.
• Patients must have relapsed or refractory disease after attaining at least a first remission. They may be in first to third relapse..
• Patients with Philadelphia chromosome t(9;22) positive disease must have received at least two prior tyrosine kinase inhibitors.
• Patients who have experienced their relapse after a Hematopoietic stem cell transplantation (HSCT) are eligible, provided they have no evidence of graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time of enrollment.
• Prior anthracycline lifetime cumulative exposure: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy. 1. Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2 for anthracycline calculation worksheet). 2. Cohorts B & C: There is no limit on prior anthracycline exposure.
• Hematopoietic growth factors: It must have been at least seven days since the completion of therapy with granulocyte colony-stimulating factor (GCSF) 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®).
• Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond seven 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 or vice chair.
• Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of the antibody must have elapsed after the last dose of monoclonal antibody. (e.g., Rituximab = 66 days, Epratuzumab = 69 days)
• Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines, chimeric antigen receptor T-cells.
• Recent prior chemotherapy: At least 10 days after standard vincristine and the completion of any type of chemotherapy induction regimen. At least 3 weeks after radiation therapy. At least 30 days after the completion of any investigational neoplastic agent is also required. An investigational agent is defined as any drug that is not approved and licensed for sale by the FDA for institutions in the United States, by Health Canada for institutions in Canada and by The Therapeutic Goods Administration for institutions in Australia. Exceptions:
• There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such; it is allowable to enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose disease relapse. The IT therapy given within 14 days of initiation of protocol specified chemotherapy, may substitute for the day 1 IT in cohorts A and B
• Subjects with rapidly progressive disease may receive hydroxyurea until they begin study therapy;
• Patients who relapse while on maintenance-type ALL therapy or are receiving maintenance therapy for disease stabilization will not require a wash-out period before entry into this study. However, there must be at least 10 days after any dose of standard vincristine. Renal and Hepatic Function
• Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times normal, the patient must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour creatinine clearance may also be used.
• Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be < 5 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN). Cardiac Function -Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by echocardiogram, cardiac MRI or multigated acquisition scan (MUGA). Reproductive Function
• Female patients must not be pregnant and those of childbearing potential must have a negative urine or serum pregnancy test confirmed within one week prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of childbearing potential must agree to use an effective method of contraception during the study. Exclusion Criteria Patients will be excluded if they have isolated testicular disease. Patients will be excluded if they have previously received Marqibo®. Patients will be excluded if they have a known allergy to any of the drugs used in the study, with the exception that patients with an allergy to PEG-asparaginase who can receive Erwinia asparaginase are eligible. Patients unable to receive any formulation of asparaginase may only enroll on cohort C Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment. Patients who require azole antifungal agents will be excluded. Azoles must be discontinued at least one week prior to the start of Marqibo®. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, another investigational agent or immunotherapy during the study period. Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from any cause will be excluded. Patients will be excluded if they have, significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or adherence with the protocol treatment or procedures or interfere with consent, study participation, follow up, or interpretation of study results.Patients with Down syndrome will not be eligible for enrollment on Cohort A Patients with a known history of human immunodeficiency virus (HIV) will will be excluded due to the increased risk of complications such as severe infection and unknown interaction of Marqibo® with antiretroviral drugs. Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above the ULN per the institution normal ranges).

• Gestational age 29 0/7 to 33 6/7 weeks at birth
• Birth weight less than 1600 grams
• Greater than 48 hours of age
• Current weight less than 1540 grams
• In an incubator
• Receiving phototherapy
• Receiving respiratory support (including CPAP, ventilation, HFNC > 2 LPM)
• Receiving blood pressure support
• Designated for transfer to referral hospital while in incubator
• Known major congenital or chromosomal anomaly

• Patients must have constitutional trisomy 21 (Down syndrome) or trisomy 21 mosaicism (by karyotype or fluorescence in situ hybridization [FISH])
• Patient has one of the following:
• Patients has previously untreated de novo AML and meets the criteria for AML with >= 20% bone marrow blasts as set out in the World Health Organization (WHO) Myeloid Neoplasm classification
• Attempts to obtain bone marrow either by aspirate or biopsy must be made unless clinically prohibitive; in cases where it is clinically prohibitive, peripheral blood with an excess of 20% blasts and in which adequate flow cytometric and cytogenetics/FISH testing is feasible can be substituted for the marrow exam at diagnosis
• Patients has cytopenias and/or bone marrow blasts but does not meet the criteria for the diagnosis of AML (WHO Myeloid Neoplasm classification) because of < 20% marrow blasts and meets the criteria for a diagnosis of myelodysplastic syndrome (MDS)
• Patients has a history of transient myeloproliferative disorder (which may or may not have required chemotherapy intervention), who:
• Are > 8 weeks since resolution of transient myeloproliferative disease (TMD) with >= 5% blasts, OR
• Patients who have an increasing blast count (>= 5%) in serial bone marrow aspirates performed at least 4 weeks apart
• Children who have previously received chemotherapy, radiation therapy or any anti-leukemic therapy are not eligible for this protocol, with the exception of cytarabine for the treatment of TMD
• There are no minimal organ function requirements for enrollment on this study
• Note: Previous cardiac repair with sufficient cardiac function is not an exclusion criteria
• Each patient?s 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 subjects research must be met
• Patients with promyelocytic leukemia (French-American-British [FAB] M3)
• Prior therapy
• Patients =< 30 days from the last dose of cytarabine used for treatment of TMD

• Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease; the diagnosis is made based on the following criteria
• JMML category 1 (all of the following): the diagnostic criteria must include all features in category 1 and EITHER (i) one of the features in category 2 OR (ii) two features from category 3 to make the diagnosis
• Splenomegaly
• > 1000 (1 x 10^9/uL) circulating monocytes
• < 20% blasts in the bone marrow or peripheral blood
• Absence of the t(9;22) or BCR/ABL fusion gene
• JMML category 2 (at least one of the following if at least two category 3 criteria are not present):
• Somatic mutation in RAS or PTPN11
• Clinical diagnosis of NF1 or NF1 gene mutation
• Homozygous mutation in CBL
• Monosomy 7
• JMML category 3 (at least two of the following if no category 2 criteria are met):
• Circulating myeloid precursors
• White blood cell count, > 10 000 (10 x 10^9/ uL)
• Increased hemoglobin F for age
• Clonal cytogenetic abnormality
• GM-CSF hypersensitivity
• Patients with refractory or relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (DNA) demethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality; frontline therapy is defined as one cycle of intravenous chemotherapy that includes of any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine; frontline therapy will also include any conditioning regimen as part of a stem cell transplant; patients who transform to AML at any point with more than 20% blasts are not eligible for this trial
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky 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
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment
• Myelosuppressive chemotherapy: patients must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea
• Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy
• Hematopoietic growth factors: at least 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
• Biologic (anti-neoplastic agent): at least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
• Monoclonal antibodies:
• At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines
• At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody
• Radiotherapy:
• >= 2 weeks must have elapsed since local palliative external radiation therapy (XRT) (small port)
• >= 6 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if traumatic brain injury (TBI) was received
• >= 4 weeks must have elapsed if other substantial bone marrow irradiation was given
• Stem cell transplant or rescue without TBI: no evidence of active graft versus (vs.) host disease and >= 3 months must have elapsed since transplant
• Patients must not be known to be refractory to red blood cell or platelet 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 (must be performed within 7 days prior to enrollment):
• Age: Maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male) 0.4 (female)
• 6 months to < 1 year: 0.5 (male) 0.5 (female)
• 1 to < 2 years: 0.6 (male) 0.6 (female)
• 2 to < 6 years: 0.8 (male) 0.8 (female)
• 6 to < 10 years: 1 (male) 1 (female)
• 10 to < 13 years: 1.2 (male) 1.2 (female)
• 13 to < 16 years: 1.5 (male) 1.4 (female)
• >= 16 years: 1.7 (male) 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (=< 135 U/L) (for the purpose of this study, the ULN for SGPT is 45 U/L) (must be performed within 7 days prior to enrollment)
• Serum albumin >= 2 g/dL (must be performed within 7 days prior to enrollment)
• Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA)
• Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs
• Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed
• Patients who are pregnant or breast-feeding are not eligible for this study as there is yet no available information regarding human fetal or teratogenic toxicities; negative pregnancy tests must be obtained in girls who are post-menarchal; patients of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; women of childbearing potential should be advised to use effective contraception for 4 months after the last dose of trametinib; trametinib may also potentially be secreted in milk and therefore breastfeeding women are excluded; female patients should not breastfeed during treatment with trametinib, and for 4 months following the last dose; male patients must use a condom during intercourse and agree not to father a child during therapy and for 4 months following discontinuation of trametinib to avoid unnecessary exposure of trametinib to the fetus
• Concomitant Medications
• Corticosteroids: patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 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
• Note: hydrocortisone used as a pre-medication to prevent transfusion related reactions is not considered a concomitant corticosteroid
• 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 patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
• Anti-graft versus host disease (GVHD) or agents to prevent organ rejection post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
• Cardiac medications: any medications for treatment of left ventricular systolic dysfunction
• Patients who have an uncontrolled infection 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
• Patients with a history of hepatic sinusoid obstructive syndrome (veno-occlusive disease) within the prior 3 months
• Patients with a history of current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
• Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension)
• Uncontrolled systemic disease(s) such as hypertension or diabetes mellitus; blood pressure must be =< the 95th percentile for age, height, and gender
• History of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib
• Patients who are able to swallow capsules or liquid or able to use a nasogastric or G tube are eligible

• Age ≤6 weeks (≤42 days) at time of dose
• Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test
• Compound muscle action potential (CMAP) ≥2mV at Baseline; centralized review of CMAP data will be conducted
• Gestational age of 35 to 42 weeks
• Patients with pre-symptomatic SMA Type 1 as determined by the following features: − 2 copies of SMN2 Patients with 2 copies of SMN2 (n ≥12)
• Patients with pre-symptomatic SMA Type 2 as determined by the following features:
• 3 copies of SMN2
• Weight at screening visit <2 kg
• Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation <92% awake or asleep without any supplemental oxygen or respiratory support at the screening visit
• Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA
• Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory support at any time and for any duration prior to screening or during the screening period
• Patients with signs of aspiration/inability to tolerate nonthickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
• Clinically significant abnormalities in hematology or clinical chemistry parameters as determined by investigator or medical monitor
• Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
• Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
• Biological mother with active viral infection as determined by screening laboratory samples (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C) • Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease Control and Prevention (CDC) Zika virus epidemiological criteria including history of residence in or travel to a geographic region with active Zika transmission at the time of travel will be tested for Zika virus RNA. Positive results warrant confirmed negative Zika virus RNA testing in the patient prior to enrollment.
• Serious nonrespiratory tract illness requiring systemic treatment and/or hospitalization within 2 Weeks prior to screening
• Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 Weeks prior to dosing
• Severe nonpulmonary/respiratory tract infection within 4 Weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Investigator or Sponsor medical monitor, creates unnecessary risks for gene replacement therapy such as:
• Major renal or hepatic impairment
• Known seizure disorder
• Diabetes mellitus
• Idiopathic hypocalciuria
• Symptomatic cardiomyopathy
• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
• Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 4 Weeks prior to gene replacement therapy
• AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay • Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may receive retesting inside the 30-Day screening period and will be eligible to participate if the AntiAAV9 antibody titer upon retesting is ≤1:50, provided the <6 Week age requirement at the time of dosing is still met
• Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior to dosing

Key
• Heterozygous for the F508del mutation (F/MF)
• Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for age, sex, and height Key
• Clinically significant cirrhosis with or without portal hypertension
• Lung infection with organisms associated with a more rapid decline in pulmonary status
• Solid organ or hematological transplantation Other protocol defined Inclusion/Exclusion criteria may apply

1. Age (at the time of consent/assent): ≥6 months to ≤18 years
•Cohort 4 only: ≥10 years to ≤18 years 2. Performance Status:
• If <12 years of age: Lanksy Performance Status >50%
• If ≥12 years of age: Karnofsky Performance Status >50% NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status. 3. Has provided written informed consent 4. Has a life expectancy of >3 months 5. Has relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician's discretion 6. Is ineligible or inappropriate for other treatment regimens known to have effective potential 7. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or equivalent laboratory certification 8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment 9. Has completed a prior therapy (ies) according to the criteria below:
• Other investigational study agent (any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric) (At least 30 days or five half-lives, whichever is longer, since last dose prior to the first dose of tazemetostat)
• Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat)
• Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat)
• Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat)
• Monoclonal antibody (ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat)
• Immunotherapy (e.g., tumor vaccine) At least 6 weeks since last dose of immunotherapy agent(s) prior to first dose of tazemetostat)
• Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereotactic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥ 50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat)
• Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat)
• Hematopoietic cell transplantation (At least 60 days from infusion of hematopoietic cells prior to first dose of tazemetostat) 10. Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below:
• Hematologic (BM Function):
• Hemoglobin ≥ 8 g/dL
• Platelets ≥100,000/mm^3 (≥100 x 10^9/L)
• ANC ≥1,000/mm^3 (≥1.0 x 10^9/L)
• Hematologic (Coagulation Factors):
• INR/ PTd ≤1.5 ULN
• PTT ≤1.5 ULN
• Fibrinogen ≥0.75 LLN
• Renal Function (creatinine clearance or serum creatinine):
• Calculated creatinine clearance ≥50 mL/min/1.73m^2
• Serum creatinine 6 months to 1 year: male 0.6 mg/dL (53 µmol/L) female 0.5 mg/dL (44 µmol/L)
• Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 µmol/L) female 0.6 mg/dL (53 µmol/L)
• Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 µmol/L) female 0.8 mg/dL (71 µmol/L)
• Serum creatinine 6 to <10 years: male 1 mg/dL (88 µmol/L) female 1 mg/dL (88 µmol/L)
• Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 µmol/L) female 1.2 mg/dL (106 µmol/L)
• Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 µmol/L) female 1.4 mg/dL (125 µmol/L)
• Serum creatinine ≥16 years: male 1.7 mg/dL (150 µmol/L) female 1.4 mg/dL (125 µmol/L)
• Hepatic Function:
• Total bilirubin <1.5 x ULN
• ALT or AST <3 x ULN Eligibility can be determined by either total or conjugated bilirubin 11. For subjects with CNS involvement: Subjects must have deficits that are stable for a minimum of 14 days prior to enrollment, or seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 7 days prior to enrollment NOTE: Subjects with leptomeningeal disease or brian tumors with positive cerebral spinal fluid cytology are eligible for this study. Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to enrollment. 12. Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram or multi-gated acquisition scan and New York Heart Association Class<2 13. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec 14. Is able to swallow and retain orally administered medication and does not have any uncontrolled gastrointestinal (GI) condition such as nausea, vomiting, or diarrhea, or any clinically significant GI abnormalities that may alter absorption such as malabsorption syndromes, hereditary fructose intolerance, glucose-galactose malabsorption, sucrose-isomaltase insufficiency, or major resection of stomach and/or bowels NOTE: Nasogastric and gastrostomy tube administration of the oral suspension formulation of study drug is permitted. 15. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of immunohistochemistry and/or cytogenetics/fluorescence in situ hybridization (FISH) and/or deoxyribonucleic acid mutation analysis (required for study entry but enrollment based on local results) 16. Is willing and able to comply with all aspects of the protocol as judged by Investigator 17. For female subjects of childbearing potential: Subject must:
• Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of Screening and within 72 hours prior to planned first dose of tazemetostat (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and
• Agree to use effective contraception, as defined in Section 8.5.11 start of Screening until 30 days following the last dose of study treatment and have a male partner who uses a condom, or
• Practice true abstinence (when this is in line with the preferred and usual lifestyle of the subject, see Section 8.5.11, or
• Have a male partner who is vasectomized with confirmed azoospermia 18. For male subjects with a female partner of childbearing potential: Subject must:
• Be vasectomized or
• Agree to use condoms as defined in Section 8.5.11 from first dose of tazemetostat until 30 days following the last dose of tazemetostat, or
• Have a female partner who is NOT of childbearing potential For Dose Escalation Only: To be eligible for enrollment in dose escalation, a subject must meet ALL of the following criteria in addition to the inclusion criteria listed above for all subjects: 1. Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination and other lesions such as bone lesions, leptomeningeal disease, ascites, hepatosplenomegaly from disease. 2. Has one of the following histologically confirmed tumors: (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available)
• Rhabdoid tumor:
• ATRT
• MRT
• RTK
• Selected tumors with rhabdoid features
• NI1-negative tumor:
• Epithelioid sarcoma
• Epithelioid malignant peripheral nerve sheath tumor
• Extraskeletal myxoid chondrosarcoma
• Myoepithelial carcinoma
• Renal medullary carcinoma
• Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval
• Synovial sarcoma with SS18-SSX rearrangement (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available) 3. For subjects with ATRT, MRT, RTK, or selected tumors with rhabdoid features only: the following test results must be available: Morphology and immunophenotypic panel consistent with rhabdoid tumor and Loss of INI1 or SMARCA4 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable 4. For subjects with INI1 negative tumor only: the following test results must be available: Morphology and immunophenotypic panel consistent with INI1-negative tumors, and Loss of INI1 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable 5. For subjects with synovial sarcoma only: The following test results must be available: Morphology consistent with synovial sarcoma, and Cytogenetics or FISH and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11) For Dose Expansion Only: Note: To be eligible for enrollment in Dose Expansion, a subject must meet ALL of the following criteria in addition to the inclusion criteria for ALL subjects listed above 1. Has measurable disease 2. Has one of the following histologically confirmed tumors:
• Cohort 1
•ATRT
• Cohort 2
•MRT/RTK/selected tumors with rhabdoid features
• Cohort 3
•INI-negative tumors:
• Epithelioid sarcoma
• Epithelioid malignant peripheral nerve sheath tumor
• Extraskeletal myxoid chondrosarcoma(EMC)
• Myoepithelial carcinoma
• Renal medullary carcinoma
• Chordoma (poorly differentiated or de-differentiated)
• Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval
• Cohort 4
•Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement To be eligible for enrollment in Dose Expansion, a subject must meet All of the following criteria in addition to the inclusion criteria for All subjects listed above. NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP or other Sponsor-approved certified laboratory must be available. 3. For subjects with ATRT/MRT/RTK only
•have the following test results available:
• Morphology and immunophenotypic panel consistent with rhabdoid tumor, and
• Loss of INI1 or SMARCA4 confirmed by IHC, or
• Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable 4. For subjects with INI1-negative tumors only: The following test results must be available:
• Morphology and immunophenotypic panel consistent with INI1-negative tumors, and
• Loss of INI1 confirmed by IHC, or
• Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable 5. For subjects with synovial sarcoma only: The following test results must be available:
• Morphology consistent with synovial sarcoma, and
• Cytogenetics or FISH and/or molecular confirmation (e.g., deoxyribonucleic acid [DNA] sequencing) of SS18 rearrangement t(X;18)(p11;q11) 6. For subjects to be enrolled in Cohort 4: Able to swallow and retain orally administered tablets 1. Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2 2. Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy 3. Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat 4. Has had major surgery within 2 weeks prior to enrollment NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 2 weeks prior to enrollment. 5. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing. Note: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central lab. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy. 6. Has a prior history of T-LBL/T-ALL. 7. Has clinically active heart disease including prolonged corrected QTcF (>450 msec) 8. Is currently taking any prohibited medication(s) 9. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study 10. Has an active infection requiring systemic treatment 11. Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus (HIV) 12. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA) 13. Has had a symptomatic venous thrombosis within the 14 days prior to study enrollment NOTE: Subjects with a history of a deep vein thrombosis 14 days prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study 14. For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral hemorrhage of more than punctate size on Screening MRI obtained within 14 days of starting study drug,or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents 15.15. Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben 16. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements 17. For female subjects of childbearing potential: Is pregnant or nursing For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of tazemetostat.

Accrual Objective: N=10 adults, 25 children) STUDY INCLUSION CRITERIA:
• Subjects fulfilling all of the following criteria are eligible for enrollment as study participants for Phase 1a and Phase 2: 1. Subject and/or parent guardian must be able to understand and provide informed consent. 2. Male or female adults, 18 through 55 years of age at recruitment (Phase 1) or male or female children, 8‐14 years of age at recruitment (Phase 2). 3. Have a history of asthma for a minimum of 1 year before study entry: 1. A diagnosis of asthma for this study is defined as a reported clinical diagnosis of asthma made by a physician over a year ago. 2. The subject must have persistent asthma defined by the current need for at least 100 microgram (mcg) fluticasone per day or the equivalent of another inhaled corticosteroid. 3. The subject's asthma must be well controlled as defined by:
• A Forced Expiratory Volume in 1 Second (FEV1) ≥ 80% predicted.
• An Asthma Control Test (ACT) score ≥ 20. 4. Are sensitive to German Cockroach as documented by a positive (≥ 3 mm greater than negative control) skin prick test result and a positive German Cockroach specific immunoglobulin E (IgE) (≥0.35 kUA/L). 5. Have no known contraindications to the allergenic extracts or diluents.
• Subjects who meet the following criteria are eligible for enrollment as study participants in Phase 1b after completion of Phase 1a: 1. Their asthma must be well controlled as defined by: 1. A FEV1 ≥ 80% predicted. 2. An Asthma Control Test (ACT) score ≥ 20. 2. The subject tolerated the Nasal Allergen Challenge (NAC) during Phase 1a with no adverse events grade 2 or higher as determined by "Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (published September 2007) for local reactions to study procedures."
• Subjects not eligible for enrollment as study participants in Phase 1b after completion of Phase 1a if any of the following criteria are met: 1. Are pregnant or lactating. 2. Have an asthma severity classification of severe persistent, using the NAEPP classification, as evidenced by at least one of the following: 1. Require a dose of greater than 500 mcg of fluticasone per day or the equivalent of another inhaled corticosteroid. 2. Have received more than 2 courses of oral or parenteral corticosteroids within the last 12 months or one course within the last 3 months. 3. Have been treated with depot corticosteroids within the last 12 months. 4. Have been hospitalized for asthma within the 12 months prior to their participation in Phase1b. 5. Have had an emergency room visit for asthma within the 3 months prior to their participation in Phase 1b. 6. Have had a life‐threatening asthma exacerbation that required intubation, mechanical ventilation, or that resulted in a hypoxic seizure within 2 years prior to their participation in Phase 1b. 3. Have received allergen immunotherapy (SLIT or SCIT) in the last 12 months prior to their participation in Phase 1b. 4. Have previously been treated with anti‐IgE therapy in the 12 months prior to their participation in Phase 1b. 5. Are currently receiving oral or nasal antihistamines, nasal corticosteroids, nasal decongestants, nasal anticholinergics or cromolyn, which cannot be suspended for the required washout periods prior to the nasal allergen challenge in Phase 1b. 6. Have received an investigational drug in the 30 days prior to their participation in Phase 1b. 7. Have past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the subject's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. 8. Meet any of the Participant Stopping Rules and Withdrawal Criteria during Phase 1a
• The participant elected to withdraw consent from all future study activities, including followup.
• The Investigator no longer believes participation is in the best interest of the participant.
• Serious Adverse Event (SAE) related to investigational product.
• Anaphylactic reaction grade 2 or 3.
• Inability to tolerate the NAC prior to reaching a TNSS ≥8 due to excessive discomfort or symptoms.
• Epistaxis occurring during the Challenge Visit.
• The need to start immunotherapy or any chronic immunosuppressive medications in the period between Phase 1a and Phase 1b.
• Require a dose of greater than 500 mcg of fluticasone per day or the equivalent of another inhaled corticosteroid to maintain asthma control in the period between Phase 1a and Phase 1b.
• Inability to restrict use of antihistamines, nasal steroids, nasal decongestants, nasal anticholinergics or cromolyn prior to the NAC.
• Development of any serious medical illness whose natural history, sequela, or treatment would be worsened or impaired by continuation in the protocol.
• Subject is "lost to follow‐up" 9. The subject's initial TNSS at the Repeat Challenge Visit must be within 1 point of the initial TNSS at the Challenge Visit in Phase 1a. If the participant's initial TNSS is outside the 1 point range, then the participant may be reevaluated for the Repeat Challenge Visit up to 3 additional times. STUDY EXCLUSION CRITERIA: Subjects fulfilling any of the following criteria are not eligible for enrollment in any portion of the study and may not be reassessed. Participants are ineligible if they: 1. Plan to move from the area during the study period. 2. Have a history of idiopathic anaphylaxis or anaphylaxis grade 2 or higher as defined by the grading scale of Brown et al. for anaphylaxis and systemic reactions to study procedures. 3. Have unstable angina, significant arrhythmia, uncontrolled hypertension, history of autoimmune disease, or other chronic or immunological diseases that in the opinion of the investigator might interfere with the evaluation of the investigational agent or pose additional risk to the participant. 4. Are using tricyclic antidepressants or beta‐adrenergic blocker drugs (both oral and topical). EXCLUSION CRITERIA SPECIFIC TO STUDY PHASE 1A AND -2:
• Subjects who meet any of these criteria are not eligible for enrollment as study participants in Phase1a and Phase 2: 1. Are pregnant or lactating. Post‐menarcheal females must be abstinent or use a medically acceptable birth control method throughout the study (e.g. oral, subcutaneous, mechanical, or surgical contraception). 2. Cannot perform spirometry at Screening. 3. Have an asthma severity classification at Recruitment of severe persistent, using the The National Asthma Education and Prevention Program (NAEPP) classification, as evidenced by at least one of the following: 1. Require a dose of greater than 500mcg of fluticasone per day or the equivalent of another inhaled corticosteroid. 2. Have received more than 2 courses of oral or parenteral corticosteroids within the last 12 months or one course within the last 3 months. 3. Have been treated with depot corticosteroids within the last 12 months. 4. Have been hospitalized for asthma within the 12 months prior to recruitment. 5. Have had an emergency room visit for asthma within the 3 months prior to recruitment. 6. Have had a life‐threatening asthma exacerbation that required intubation, mechanical ventilation, or that resulted in a hypoxic seizure within 2 years prior to recruitment. 4. Have nasal polyps or other major structural abnormalities in their nasal cavities as assessed by anterior rhinoscopy. 5. Have active rhinitis symptoms prior to the nasal allergen challenge, defined as a Baseline Total Nasal Symptom Score(TNSS) >3,with no individual symptom score >1. 6. Do not have access to a phone (needed for scheduling appointments). 7. Have received allergen immunotherapy (Sublingual [SLIT] or Subcutaneous [SCIT]) in the last 12 months prior to recruitment or who plan to initiate or resume allergen immunotherapy during the study. 8. Have previously been treated with anti‐IgE therapy in the 12 months prior to recruitment. 9. Are currently receiving oral or nasal antihistamines, nasal corticosteroids, nasal decongestants,nasal anticholinergics or cromolyn, which cannot be suspended for the required washout periods prior to skin prick testing and the nasal allergen challenge. 10. Have received an investigational drug in the 30 days prior to recruitment or who plan to use an investigational drug during the study. 11. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

INCLUSION CRITERIA -Patients must be greater than or equal to 12 months and ≤ 21 years of age at the time of study enrollment. Patients must have one of the following: Leukemia
• Patients must have relapsed or refractory acute lymphoblastic leukemia (ALL) with greater than or equal to 25% blasts in the bone marrow (M3). OR
• Patients may have an M2 marrow (greater than or equal to 5% to < 25% blasts) with an extramedullary site of relapse; including CNS 2 and CNS 3.
• Refractory disease defined as no more than 1 prior failed salvage attempt following the current relapse, or no more than 2 additional treatment cycles after initial induction failure in newly diagnosed patients. Lymphoma
• Patient must have relapsed or refractory lymphoblastic lymphoma or peripheral T-cell lymphoma.
• Patient must have histologic verification of disease at original diagnosis.
• Patient must have evaluable or measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry.
• Patients may have CNS 2 or 3 disease, if other sites of involvement. Karnofsky greater than or equal to 50% for patients > 16 years of age and Lansky greater than or equal to 50 for patients ≤ 16 years of age. Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy. Patients must have had 2 or more prior therapeutic attempts defined as:
• Relapse after going into remission from re-induction for the first or subsequent relapse (ie: 2nd , 3rd, 4th…relapse), or
• Patients with lymphoma may have refractory disease after first or greater relapse and a single re-induction attempt. Patients with leukemia or lymphoma who relapse while receiving maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study. At least 14 days must have elapsed after the completion of cytotoxic therapy, with the exception of hydroxyurea. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor. Biologic (anti-neoplastic agent): At least 7 days after 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 Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines. or chimeric antigen receptor T cell (CART) therapy. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of a monoclonal antibody. (ie: Rituximab = 66 days, Epratuzumab = 69 days). Patients must have been off blinatumomab infusion for at least 7 days and all drug-related toxicity must have resolved to grade 2 or lower as outlined in the inclusion and exclusion criteria XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of pelvis; At least 42 days must have elapsed if other substantial marrow radiation. Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84 days must have elapsed after transplant or stem cell infusion. Study specific limitations on prior therapy: Patient may not have received therapy with an mTOR inhibitor. Adequate Bone Marrow Function Defined as: Blood counts are not required to be normal prior to enrollment on trial. However, platelet count must be greater than or equal to 20,000/mm3 to initiate therapy (may receive platelet transfusions). Patients should not be known to be refractory to red blood cell or platelet transfusions. Adequate Renal Function Defined as:
• Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 or
• Normal serum creatinine based on age and gender. Adequate Liver Function Defined as:
• Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to 1.5 x normal per institutional normal values for age.
• SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit of normal (Grade 1 or less per CTCAE 4). --GGT must be less than 2.5 x institutional upper limit of normal (Grade 1 or less per CTCAE 4).
• Serum albumin greater than or equal to 2 g/dL.
• The hepatic requirements may be waived for patients with elevations clearly due to leukemic infiltration after consultation with the Study Chair or Vice Chair.
• Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum cholesterol level ≤ 300 mg/dL. Adequate Cardiac Function Defined As:
• Shortening fraction of ≥ 27% by echocardiogram, or
• Ejection fraction of ≥ 50% by gated radionuclide study. Adequate Pulmonary Function Defined as:
• Pulse oximetry > 94% on room air (> 90% if at high altitude)
• No evidence of dyspnea at rest and no exercise intolerance.
• Baseline chest x-ray with no evidence of active infectious disease or pneumonitis. Reproductive Function
• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.
• Random or fasting glucose within the upper limits of normal for age. If the initial blood glucose is non-fasting and above normal limits a fasting glucose can be obtained and must be within the upper limits of normal for age. EXCLUSION CRITERIA
• 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.
• Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible. The definition of "investigational" for use in this protocol means any drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods Administration to be sold in the countries they govern. (United States, Canada and Australia)
• Anti-cancer Agents: Patients who are currently receiving or may receive while on therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible [except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of study therapy.
• Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post transplant are not eligible for this trial. At least 3 half-lives must have elapsed after the last dose of GVHD meds.
• Anticoagulants: Patients who are currently receiving therapeutic anticoagulants (including aspirin, low molecular weight heparin, and others) are not eligible. At least 3 half-lives must have elapsed after the last dose of anticoagulants.
• Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently receiving ACE inhibitors are not eligible due to the development of angioneurotic edema-type reactions in some subjects who received concurrent treatment with temsirolimus + ACE inhibitors. At least 3 half-lives must have elapsed after the last dose of ACE inhibitors.
• Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme inducing anticonvulsants (ie phenytoin, phenobarbitol, or carbamazepine) are not eligible. Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie: gabapentin or levetiracetam) prior to study entry is acceptable. At least 3 half-lives must have elapsed after the last dose of enzyme inducing anti-coagulants.
• Patients receiving treatment with azoles such as fluconazole or voriconazole which are potent inhibitors of temsirolimus metabolism. At least 3 half-lives must have elapsed after the last dose of azoles. Infection Criteria Patients are excluded if they have:
• Positive blood culture within 48 hours of study enrollment;
• Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
• A positive fungal culture within 30 days.
• Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed. Patients with Down syndrome and Fanconi Anemia are excluded. Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with protocol treatment or required observations, interfere with consent, study participation, follow up, or interpretation of study results. Patients with known optic nerve and/or retinal involvement (because it may not be possible to safely delay irradiation) are not eligible. Patients presenting with visual disturbances by history or physical exam should have an ophthalmological exam and, if indicated, an MRI to determine optic nerve or retinal involvement.

• ≥ 36 weeks of gestational age
• Receiving active or passive whole body cooling/hypothermia since < 6 hours of age
• Perinatal depression based on at least one of the following: 1. Apgar score < 5 at 10 minutes, or 2. Need for resuscitation at 10 minutes (i.e., chest compressions, or positive pressure respiratory support including endotracheal, mask ventilation, or CPAP), or 3. pH < 7.00 in cord gas (arterial or venous) or in an infant gas (arterial or venous) obtained at < 60 minutes of age, or 4. Base deficit ≥ 15 mmol/L in cord gas (arterial or venous) or in an infant gas (arterial or venous) obtained at < 60 minutes of age
• Moderate to severe encephalopathy (based on modified Sarnat exam) present between 1-6 hours after birth
• Study drug unlikely to be administered within 26 hours of birth
• Infant has living twin (or higher order multiple) who is also being cooled
• Birth weight < 1800 g (e.g., intrauterine growth restriction)
• Genetic or congenital condition that affects neurodevelopment or requires multiple surgeries (e.g., congenital viral infection, hydrops, complex congenital heart disease, severe dysmorphic features, etc.)
• Head circumference < 30 cm
• Redirection of care is being considered due to moribund condition
• Patient anticipated to be unavailable for evaluation at age 2
• Polycythemia (hematocrit > 65.0%)
• Parents/legal guardians with diminished capacity and autonomy
• Infant is participating or intends to participate in another interventional study during the birth hospitalization (note: does not include observational studies)
• Sentinel event and encephalopathy occurred only after birth
• Unable to consent in primary language of parent(s)

• Patients must be newly diagnosed and have a confirmed molecular diagnosis of classical histologic type (non large cell/anaplastic [LC/A]) WNT medulloblastoma from rapid central pathology screening review on APEC14B1 (immunohistochemistry [IHC]/molecular screening [positive nuclear beta (B)-catenin by IHC and positive for catenin beta 1 [CTNNB1] mutation) and confirmation of =< 1.5 cm^2 maximal cross-sectional area of residual tumor from rapid central imaging review
• Patient must have negative lumbar cerebrospinal fluid (CSF) cytology; CSF cytology for staging should be performed preferably 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
• Note: patients with positive CSF cytology obtained prior to 14 days after surgery may have cytology repeated to determine eligibility and final CSF status
• Patients must have eligibility confirmed by rapid central imaging review on APEC14B1; standard whole brain magnetic resonance imaging (MRI) with and without contrast (gadolinium) and spine MRI with contrast (gadolinium) must be performed at the following time points:
• Pre-operative to include an MRI of the brain with and without contrast (including post-contrast three-dimensional [3D] T1-weighted image [T1WI] and post-contrast fluid-attenuated inversion recovery [FLAIR])
• Pre-operative spinal MRI with gadolinium; post-operative staging spinal MRI may be obtained if pre-operative imaging is not possible or is suboptimal; pre-operative spine imaging is strongly preferred, due to the potential of post-operative sequelae, which could affect metastasis detection
• Post-operative brain MRI within 72 hours of surgery
• Patients must be enrolled on ALTE07C1 prior to enrollment on ACNS1422
• Patients must be enrolled within 36 days of definitive diagnostic surgery (day 0)
• Note: patients must begin treatment within 36 days of definitive surgery
• Patients must have no previous radiotherapy or chemotherapy other than corticosteroids
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• Platelet count >= 100,000/uL (transfusion independent)
• Hemoglobin >= 10.0 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]) =< 110 U/L (for the purpose of this study, the upper limit of normal [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
• 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 tumor-directed therapy other than surgical intervention and corticosteroids
• Female patients who are pregnant are ineligible
• 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 must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on ANBL1531
• 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 age or 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 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; 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

Inclusion Criteria 1. Subjects ≥ 6 years of age at time of Informed Consent Form (ICF) or Assent Form signing. 2. Confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus one of the following: 1. Positive sweat chloride test (value ≥ 60 mEq/L), 2. Genotype with 2 mutations consistent with CF (i.e., a mutation in each of the cystic fibrosis transmembrane conductance regulator [CFTR] genes). 3. Positive sputum culture or a throat swab culture for MRSA at Screening. 4. In addition to the Screening sample, have at least 2 prior sputum or throat swab cultures positive for MRSA, of which at least 1 sample is more than 6 months prior to Screening. At least 50% of all MRSA cultures (sputum or throat swab culture) collected from the time of the first positive culture (in the previous 1 year) must have tested positive for MRSA. (Note: Screening sample may count towards 50% positive count) 5. Forced expiratory volume in 1 second (FEV1) ≥ 30% and ≤ 90% of predicted that is normal for age, gender, race, and height, using the Global Lung Function Initiative (GLI) equation. 6. At least 1 episode of acute pulmonary infection treated with non-maintenance antibiotics within 12 months prior to the Baseline visit. (Initiation of treatment with intermittent inhaled anti-Pseudomonal therapy will not qualify as treatment with non-maintenance antibiotics). 7. If female of childbearing potential, an acceptable method of contraception must be used during the study and must be combined with a negative pregnancy test obtained during Screening; sexually active male subjects of reproductive potential who are non-sterile (i.e., male who has not been sterilized by vasectomy for at least 6 months, and were not diagnosed with infertility through demonstration of azoospermia in a semen sample and/or absence of vas deferens through ultrasound) must be willing to use a barrier method of contraception, or their female partner must use an acceptable method of contraception, during the study. For purposes of this study, the Sponsor defines "acceptable methods of contraception" as: 1. Oral birth control pills administered for at least 1 monthly cycle prior to administration of the study drug. 2. A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior to the study drug administration but not beyond the 4th successive year following insertion. 3. Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 monthly cycle prior to study drug administration. 4. Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1 monthly cycle prior to administration of the study drug and continuing through 1 month following study completion. 5. Hysterectomy or surgical sterilization. 6. Abstinence. 7. Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive foam). NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal contraceptive exposure, reducing the effectiveness and increasing the incidence of menstruation-associated adverse reactions. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi. 8. Able and willing to comply with the protocol, including availability for all scheduled study visits and able to perform all techniques necessary to use the AeroVanc inhaler and measure lung function. 9. Agree not to smoke during any part of the clinical trial (Screening visit through end of study). 10. Subjects with a P. aeruginosa co-infection must either be stable on a regular suppression regimen of inhaled antibiotics or must be, in the opinion of the Investigator, stable despite the lack of such treatment. Exclusion Criteria 1. Use of anti-MRSA treatments prescribed as maintenance therapy (intravenous [IV] or inhaled treatment within 28 days; oral treatment within 14 days) prior to the Baseline visit. 2. Use of non-maintenance antibiotic for pulmonary infection or extrapulmonary MRSA infection (IV or inhaled antibiotic within 28 days; oral antibiotic within 14 days) prior to the Baseline visit. 3. History of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug or placebo except for a history of red-man syndrome. 4. Inability to tolerate inhaled products. 5. First time sputum culture or throat swab culture yielding B. cepacia, or nontuberculous Mycobacteria in the previous 6 months to Screening. 6. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation. 7. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus [VRSA], or vancomycin intermediate resistant Staphylococcus aureus [VISA], with minimum inhibitory concentration [MIC] ≥ 8 μg/mL). 8. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone every other day, or equipotent doses of other corticosteroids. 9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 14 days, or changes in CFTR modulators within 28 days, prior to the Baseline visit. 10. Abnormal laboratory findings or other findings or medical history at Screening that, in the Investigator's opinion, would compromise the safety of the subject or the quality of the study data. 11. Inability to tolerate inhalation of a short acting beta2 agonist 12. SpO2 <90% at Screening. 13. Changes in physiotherapy technique or physiotherapy scheduled within 1 week of the Baseline visit. 14. Administration of any investigational drug or device within 4 weeks prior to the Screening visit and during the study 15. Female with positive pregnancy test result during Screening, pregnant (or intends to become pregnant), lactating or intends to breastfeed during the study. 16. Renal insufficiency, defined as creatinine clearance < 50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation for children at the Screening visit. 17. Abnormal liver function, defined as ≥ 4x upper limit of normal (ULN), of serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT), or known cirrhosis at Screening. 18. Diagnosed with clinically significant hearing loss. 19. History of positive result for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). 20. Planned hospitalizations for prophylaxis antibiotic treatment within 28 days prior to Baseline visit or during the double-blind period (Period 1).

• Gestational age greater than or equal to 34 weeks at birth
• Admitted to the center NICU by 48 hours of age
• Intubated and mechanically ventilated for a minimum of 2 hours before 72 hours postnatal age
• Receiving ECMO
• Intubated for the sole purpose of anticipated surgery or airway anomalies
• Treatment will be limited based on poor prognosis
• Receiving dexamethasone or hydrocortisone
• Receiving ibuprofen or indomethacin
• Congenital heart disease
• Hypotension thought to result from specific, immediately remediable factors including placental hemorrhage, acute hemorrhage or tension pneumothorax
• Pituitary hypoplasia or congenital adrenal hyperplasia
• Any chromosomal disorder
• Hypertension in the absence of inotrope therapy as defined by mean arterial blood pressure > 95th percentile
• Initiation of whole body cooling for moderate or severe neonatal encephalopathy
• Brain disorders or any other known structural abnormality
• Major anomalies

• inborn
• birth weight <= 1250 grams
• indwelling arterial catheter in place
• age <24 hours old
• lethal chromosomal abnormality
• major congenital anomaly
• skin integrity insufficient to allow placement of NIRS sensors
• decision to not provide full intensive care

• Infants inborn at NRN centers
• <27 weeks gestational age
• Infants enrolled in one or more additional NICHD NRN Follow-up studies. For infants that do not meet the inclusion criteria above, inclusion and exclusion criteria are determined by the criteria for the additional trial(s). In these cases, infants that are larger than 1,000 grams and/or older than 27 weeks may be included in the FU Study. Note: These inclusion criteria were changed as of 1/1/2008. Prior to this date, infants with birth weights between 401 and 1500 grams who were admitted to NRN NICUs within 14 days of birth were included in the database.

• Preterm infants <29 weeks GA and SGA infants <35 weeks GA born at Parkland Health and Hospital System
• Maternal plan to breastfeed or to use milk from the donor milk bank
• From birth to 1 week of life
• Patients on comfort care only
• Patients with major congenital abnormalities
• Patients who are too unstable for the first 7 days to have an accurate length measurement

• Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate)
• Infants weight greater than or equal to 1500 grams at birth
• Postnatal age less than 6 hours
• Infants who meet clinical, biochemical and neurologic criteria for moderate to severe NE: Biochemical: Cord gas or blood gas within first hour of life with pH ≤7.00 or base deficit (BD) ≥16 mEq/L OR Acute perinatal event (e.g., abruptio placenta, cord prolapse, uterine rupture, severe FHR abnormality such as variable or late decelerations) AND Requirement for positive pressure ventilation for apnea or poor respiratory effort since birth for at least 10 minutes OR 10 minute Apgar score ≤5 AND Neurologic: Seizures OR modified Sarnat score with abnormalities in at least 3 of the 6 categories; at least one must be altered level of consciousness (lethargy or stupor/coma) as determined by a certified examiner (All infants who meet criteria for potential inclusion will undergo standard neurologic exam as for infants ≥36 wks GA being considered for hypothermia, with findings recorded)
• Receipt of sedative, analgesic or paralytic agent that may confound the qualifying neurologic exam
• Etiology of NE not likely to be hypoxic-ischemic in origin
• Major congenital anomaly that may confound outcome
• Considered to be moribund and will not be receiving full intensive care
• Equipment and/or appropriate staff not available
• Core temperature < 33.5oC for more than one hour at time of screening
• Unable to randomize by 6 hours of age
• Infant needs ECMO
• All blood gases (cord and postnatal at < 1hr of age) have a pH > 7.15 AND a base deficit < 10mEq/L

• Neonates ≤32wks GA requiring NCPAP in the delivery room or NICU for increasing respiratory distress or post-extubation from mechanical ventilation.
• Neonates requiring NCPAP for less than 48 hours
• Congenital anomalies
• Need for surgery
• Transfer to a different facility
• Grade 3-4 intraventricular hemorrhage