• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of a patient <18 years of age will provide informed consent and patients 11 to 18 years of age will provide written assent or as per participating institutional policy.
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment

Eligibility criteria for study enrollment:
• Signed Informed Consent Form (ICF) by parent(s)/guardian(s) of subjects and informed assent form (IAF) for subjects ≥7 years, or as per local or country specific guidelines or regulations.
• Male or female subjects 2 to 17 years old at Visit 1.
• Documented medical history or physician-confirmed diagnosis of IgE-mediated CMA with systemic symptoms related to ingestion of milk or dairy products.
• Subjects currently following a strict cow's milk-free diet, with no consumption of dairy or baked milk products.
• Cow's milk-specific IgE level at screening ≥10 kU/L
• Positive Skin Prick Test (SPT) to cow's milk with a largest wheal diameter ≥6 mm.
• Positive DBPCFC at screening with an eliciting dose ≤300 mg cow's milk proteins (approximately ≤9.4 mL of cow's milk).
• Negative urine pregnancy test for female subjects of childbearing potential. Female subjects of childbearing potential must agree and commit to use effective medical methods of contraception for the entire duration of their participation in the study. Sexual abstinence will be accepted as an effective method of contraception for girls below 15 years of age.
• Ability to perform spirometry procedures in accordance with the American Thoracic Society guidelines (2005) for subjects ≥6 years old. Ability to perform peak expiratory flow (PEF) measurements for subjects ≥5 years old. Subjects <8 years of age who have documented inability to adequately perform spirometry can perform only the PEF evaluation. Subjects <5 years of age may be enrolled if they had no clinical features of moderate or severe persistent asthma severity (as defined by the 2007 National Heart, Lung, and Blood Institute [NHLBI] Guidelines) within 1 year before Visit 1.
• Subjects and/or parents/guardians willing to comply with all study requirements during participation in the study.
• History of severe anaphylaxis to cow's milk resulting in hypotension, hypoxia or neurological compromise (collapse, loss of consciousness or incontinence) or requiring mechanical ventilation.
• Pregnancy or lactation.
• Spirometry forced expiratory volume in 1 second (FEV1) <80% of the predicted value at Visit 1 for subjects ≥6 years and able to perform the spirometry, or PEF <80% of predicted value at Visit 1 for subjects performing only the PEF measurements.
• Any clinical features of moderate or severe persistent asthma severity (as defined by the 2007 NHLBI guidelines) and high daily doses of inhaled corticosteroids.
• Known allergy to the Viaskin patch materials or excipients, or to any of the components of the food challenge formulas other than the cow's milk proteins.
• Allergy or known history of reaction to Tegaderm® medical dressing with no possibility to use an alternative adhesive dressing authorized by the sponsor in replacement.
• Subjects having objective symptoms to the placebo formula leading to stopping the challenge during the screening DBPCFC.
• Severe reaction during the screening DBPCFC defined as need for intubation, and/or hypotension persisting after epinephrine administration, and/or the need for >2 doses of epinephrine.
• Symptomatic allergy to pollens with symptoms during the pollen season that might interfere with the symptoms observed during the DBPCFC, if the DBPCFC is performed during the pollen season. Screening of such subjects should be made out of the pollen season.
• Inability to discontinue short-acting antihistamines for 3 days or long-acting antihistamines for 5 to 7 days (depending on the half-life) before the DBPCFC.
• Use of systemic long-acting corticosteroids within 12 weeks before Visit 1 and/or use of systemic short-acting corticosteroids within 4 weeks before Visit 1 or use of systemic long-acting or short-acting corticosteroids during screening (unless used to treat symptoms triggered by the DBPCFC or triggered by accidental allergen consumption; in the latter case DBPCFC must then be scheduled after a minimum of 7 wash-out days).
• Subjects with asthma conditions meeting 1 or several criteria below:
• Uncontrolled persistent asthma (as defined by the 2007 NHLBI guidelines) or subject being treated with a combination therapy of medium or high daily dose of inhaled corticosteroid with a long acting inhaled β2-agonist. Intermittent asthmatic subjects who require intermittent use of inhaled corticosteroids for rescue are permitted.
• At least 2 systemic corticosteroid courses for asthma within 1 year before Visit 1 or 1 oral corticosteroid course for asthma within 3 months before Visit 1, or during screening (unless used to treat symptoms triggered by the DBPCFC).
• Prior intubation/mechanical ventilation due to asthma within 2 years before Visit 1, or during screening.
• Upper respiratory infection or gastroenteritis within 7 days of DBPCFC (DBPCFC must then be rescheduled at least 7 days after resolution of these conditions).
• Any history of milk immunotherapy (eg, oral immunotherapy, sublingual immunotherapy or specific oral tolerance induction).
• Prior history of any other food allergen immunotherapy (eg, oral immunotherapy, sublingual immunotherapy or specific oral tolerance induction) within 5 years before Visit 1.
• Subjects currently under aeroallergen immunotherapy and unwilling or unable to discontinue at the time of Visit 1. Aeroallergen Immunotherapy must be discontinued at the time of Visit 1.
• Use of any anti-IgE drug (eg, omalizumab), any immunomodulatory therapy, or any biological agent therapy (eg, anti-tumor necrosis factor drugs) within 1 year before Visit 1, or during screening.
• Generalized dermatologic diseases (eg, severe atopic dermatitis, uncontrolled generalized eczema, icthyosis vulgaris) with no intact zones to apply the Viaskin patch, or urticarial and mast cells disorders such as chronic idiopathic urticaria.
• Subject and/or subject's parents/guardians with obvious excessive anxiety and unlikely to cope with the conditions of a food challenge.
• Past or current disease, including but not limited to active eosinophilic gastrointestinal disorders, autoimmune disorders, immunodeficiency, malignancy, uncontrolled disease (hypertension, diabetes, psychiatric disorder, cardiac disease), or other disorders (eg, liver, gastrointestinal, kidney, cardiovascular, pulmonary disease or blood disorder) which in the opinion of the Investigator or the sponsor may affect the subject's participation in the study or place the subject at increased risk.
• Subjects and/or parents/guardians unable to use the epinephrine auto-injector properly in spite of being adequately trained.
• Contraindicated condition for the use of epinephrine.
• Use of any investigational drug or device, or participation in another interventional clinical study within 3 months before Visit 1.
• Subjects receiving beta-blockers or Angiotensin converting-enzyme (ACE) inhibitors.
• Subjects unable to follow the protocol requirements.

• Genotypically confirmed DMD, with genetic deletion amenable to exon 45 or exon 53 skipping
• Stable dose of oral corticosteroids for at least 24 weeks
• Intact right and left biceps or 2 alternative upper muscle groups
• Mean 6MWT greater than or equal 300 meters and less than or equal to 450 meters
• Stable pulmonary function: forced vital capacity (FVC) equal to or greater than 50% predicted
• Treatment with gene therapy at any time
• Previous treatment with SMT C1100, PRO045 (BMN 045), PRO053 (BMN 053) or PRO051 (BMN 051) within 24 weeks prior to Week 1
• Current or previous treatment with any other experimental treatment (other than deflazacort) within 12 weeks prior to Week 1
• Major surgery within 3 months prior to Week 1
• Presence of other clinically significant illness Other inclusion/exclusion criteria may apply

• 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 since fetal toxicities or teratogenic effects have been noted for several of the study drugs; 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

• Age: ≥12 months to <18 years old at the time of informed consent
• Diagnosis: Histologically confirmed rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) (Grade 2 or 3), or Ewing sarcoma (EWS) which is relapsed or refractory (failed front line therapy)
• The presence of measurable disease meeting the following criteria:
• At least 1 lesion of ≥1.0 centimeter (cm) in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI).
• Lesions that have had radiotherapy must show subsequent radiographic evidence of increase in size by at least 20% to be deemed a target lesion.
• Therapeutic options: Participant's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
• Performance level: Performance score ≥50%. Karnofsky (for participants >16 years of age) or Lansky (for participants ≤16 years of age). Participants who are unable to walk because of paralysis and/or previous surgeries, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
• Participants must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer directed therapy prior to study drug administration. If, after the required time frame, the numerical eligibility criteria are met, eg, blood count criteria, the participant is considered to have recovered adequately:
• Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea).
• Anticancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil count [ANC] counts): ≥7 days after the last dose of agent.
• Monoclonal antibodies ≥ 3 half-lives must have elapsed from infusion of last dose of antibody (including checkpoint inhibitors), and toxicity related to prior antibody therapy must be recovered to Grade ≤1.
• Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor (eg, Neulasta) or 7 days for a short-acting growth factor. For agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor.
• Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons, or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total body irradiation [TBI]): ≥84 days
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion or boost infusion: ≥84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: ≥42 days
• Cellular therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T-cells, natural killer cells, dendritic cells, etc)
• Radiation therapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial BM radiation
• Radiopharmaceutical therapy (eg, radiolabeled antibody, 131I-metaiodobenzylguanidine): ≥42 days after systemically administered radiopharmaceutical therapy.
• Adequate bone marrow function, defined as:
• ANC ≥1.0 × 10^9/Liter (L)
• Platelet count ≥100 × 10^9/L (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to study drug administration)
• Hemoglobin at least 8.0 grams per deciliter (g/dL) at Baseline (blood transfusions are allowed during the screening period to correct hemoglobin values less than 8.0 g/dL) Note: As blood transfusions are permitted to meet the hemoglobin criteria, participants requiring transfusion must not be known to be refractory to red blood cell or platelet transfusions.
• Adequate renal function, defined as:
• A serum creatinine based on age/gender, derived from the Schwartz formula for estimating glomerular filtration rate (GFR)
• Or creatinine clearance or GFR ≥50 milliliters per minute (mL/min)/1.73 meters squared (m^2) based on a 12 or 24 hour urine creatinine collection
• Adequate liver function, defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT) ≤110 units per Liter (U/L). For the purpose of this study, the ULN for ALT is 45 U/L
• Serum albumin ≥2 g/dL
• Informed consent: All participants and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. Participants must be willing to comply with all aspects of the protocol.
• Pregnancy, breastfeeding, contraception: Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• Females of childbearing potential (all post pubertal females will be considered to be of childbearing potential unless they have early menopause [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]) who:
• Do not agree to use a highly effective method of contraception for the entire study period and for 6 months after study drug discontinuation, ie:
• Total abstinence (if it is their preferred and usual lifestyle);
• An intrauterine device (IUD) or intrauterine system (IUS);
• A contraceptive implant;
• An oral contraceptive (must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study and for 6 months after study drug discontinuation); or
• Do not have a vasectomized partner with confirmed azoospermia. For sites outside of the European Union (EU), it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, or the participant has commenced/adjusted/changed oral hormonal contraceptive product/dose within 4 weeks prior to study drug administration, then the participant must agree to use a medically acceptable method of contraception, ie, double barrier methods of contraception such as condoms plus diaphragm or cervical/vault cap with spermicide.
• Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period or for 3 months after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months after study drug discontinuation.
•Concomitant medications:
• Corticosteroids: Participants receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to study drug administration (except when indicated for Central Nervous System [CNS] metastases, then participants must not have received corticosteroids for at least 28 days)
• Anticancer Agents: participants who are currently receiving other anticancer agents
• Anti-GVHD agents Post-transplant: Participants who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant
• Strong CYP3A4 inducers/inhibitors
• Received prior therapy with eribulin mesylate
• Any other malignancy that required treatment (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ), within 2 years prior to study drug administration
• Has hypersensitivity to eribulin or any of the excipients
• Has a prior history of viral hepatitis (B or C) as demonstrated by positive serology (presence of antigens) or have an uncontrolled infection requiring treatment. Participants with a known prior history of hepatitis B or C may be eligible pending agreement with the sponsor.
• Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy graded according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies
• Has cardiac pathology: Participants with known congestive heart failure, symptomatic or left ventricular (LV) ejection fraction <50% or shortening fraction <27%
• Participants with congenital long QT syndrome, bradyarrhythmias, or QTc >480 msec on at least 2 separate electrocardiograms (ECGs).
• Has CNS Disease: Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to study drug administration. Confirmation of radiographic stability must be done by comparing the brain scan (CT or MRI) performed during the Screening Period, using the same imaging modality, to a brain scan performed earlier (and following local therapy where applicable). Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases. Note: CNS imaging is required to confirm eligibility for participants with a known history of CNS disease.
• Have had or are planning to have the following invasive procedures:
• Major surgical procedure or significant traumatic injury within 28 days prior to study drug administration
• Laparoscopic procedure or open biopsy within 7 days prior to study drug administration
• Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 2 days prior to study drug administration
• Core biopsy, including bone marrow biopsy, within 2 days prior to study drug administration
• Fine needle aspirate within 3 days prior to study drug administration
• Has any serious concomitant illness that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments
• Participants with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV-infected participants

1. Subjects with a diagnosis of iobenguane avid, relapsed, high-risk neuroblastoma based on revised INRC criteria who have completed at least one cycle of induction and consolidation therapy with an INRC criterion of partial response or better, and then showed new progressive disease (revised INRC criteria progressive disease) as described in Park, et al. (2017).This may include one or more of the following drugs: cyclophosphamide or ifosfamide, cisplatin or carboplatin, vincristine, doxorubicin (adriamycin), etoposide, topotecan, and/or busulfan and melphalan (sometimes used during stem cell transplant) and/or immunotherapy. (If a subject is symptomatic and for logistical reasons cannot be treated immediately with 131I-MIBG, 1 to 2 cycles of "bridging chemotherapy" or immunotherapy will be permitted. If "bridging chemotherapy" or immunotherapy is applied, approximately 4 weeks will be required for reassessment of the baseline including tumor assessment. 2. Must be therapeutic 131I-MIBG naive. 3. All soft tissue lesions identified on CT/MRI scans must be iobenguane-avid lesions on an iobenguane (123I) scan or any non iobenguane avid lesions biopsy proven to be non-tumor lesions. 4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least 2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment). 5. If a man, must agree to use an adequate contraception method as deemed appropriate by the Investigator (e.g., vasectomy, condoms) or partner using effective contraception and to not donate sperm during the study and for 90 days after receiving the last dose of study drug. 6. If a woman of childbearing potential, have a negative serum pregnancy test result prior to each dosing and, if sexually active, be practicing an effective method of birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner sterilization throughout the study. 7. Age at study entry ≥1 year. 8. Previous platelet transfusions are permitted, as long as the subject has a platelet count ≥50,000/μL without transfusion support for at least 1 week. 9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline. 10. An absolute neutrophil count ≥750/μL without growth factor for 5 days. 11. Liver function parameter results: total bilirubin ≤1.5 × upper limit of normal for age, and serum glutamic-pyruvic transaminase (alanine aminotransferase) [SGPT (ALT)] and serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) [SGOT (AST)] <3 × upper limit of normal (note that for ALT, the upper limit of normal for all sites is defined as 45 U/L). 12. Normal thyroid function as measured by T4 and TSH or have abnormal results that are not considered clinically important by the Investigator or may be receiving levothyroxine. 13. Cardiac Function: Ejection fraction (≥55%) documented by echocardiogram within 1 month prior to Visit 1 (baseline). 14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance Status Performance Status (for subjects 1 to 16 years of age) ≥50%. 15. Full recovery from the toxic effects of any prior therapy. 1. Evidence of non-avid iobenguane lesions on iobenguane (123I) scan including soft tissue disease on CT/MRI that is not iobenguane-avid. 2. Subjects with primary refractory disease. 3. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not recovered from effects of any biologic therapy. 4. Subjects that are refractory to the prior treatment regimen. 5. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant. 6. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit 1 are excluded. Those who have received allogeneic stem cell treatment more than 4 months from Visit 1 must have recovered and have no active graft versus host disease (GVHD) to be eligible. 7. History of local radiation therapy within the last 3 months. 8. History of total body irradiation. 9. Subjects do not have adequate renal function defined as adjusted serum creatinine ≥1.5 × upper limit of normal for sex and age. 10. Subjects who are on hemodialysis. 11. Pregnancy or breastfeeding. 12. Significant active infections including active hepatitis B, or hepatitis C infection, or known infection with human immunodeficiency virus (HIV) (testing for HIV is not required prior to study entry). 13. Clinically important cardiac, pulmonary, and hepatic impairment.

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 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
• Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total bilirubin > 2 × ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
• 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

• Have a diagnosis of migraine with or without aura as defined by the IHS ICHD-3 guidelines (1.1 or 1.2 according to ICHD-3 [2018]), with a history of migraine headaches of at least 6 months prior to screening.
• Participants who are taking, or are expected to take, therapeutic antibodies during the course of the study (adalimumab, infliximab, trastuzumab, bevacizumab, etc.). Prior use of therapeutic antibodies, other than antibodies to calcitonin gene-related peptide (CGRP) or its receptor, is allowed if that use was more than 12 months prior to baseline.
• Known hypersensitivity to multiple drugs, monoclonal antibodies or other therapeutic proteins, or to galcanezumab or its excipients.
• Current use or prior exposure to galcanezumab, another CGRP antibody, or CGRP receptor antibody, including those who have previously completed or withdrawn from this study or any other study investigating a CGRP antibody.
• History of persistent daily headache, cluster headache or migraine subtypes including hemiplegic (sporadic or familial) migraine and migraine with brainstem aura (previously basilar-type migraine) as defined by IHS ICHD-3.
• History of significant head or neck injury within 6 months prior to screening; or traumatic head injury at any time that is associated with significant change in the quality or frequency of their headaches, including new onset of migraine following traumatic head injury.
• Participants with a known history of intracranial tumors or developmental malformations including Chiari malformations.

• 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.

Key
• Subjects will be 1 to less than 2 years of age on Day 1 of the relevant part of the study.
• Homozygous for F508del (F/F). Key
• Any clinically significant laboratory abnormalities at the Screening Visit that would interfere with the study assessments or pose an undue risk for the subject.
• Solid organ or hematological transplantation. Other protocol defined Inclusion/Exclusion criteria may apply.

• Youth admitted to the inpatient unit at either site for a recent suicide attempt or significant suicidal ideation with a plan or intent.
• The youth and parent are able to complete assessments in English, and the youth is able to complete therapy.
• The youth currently exhibits psychosis.
• The youth currently exhibits mania.
• The youth is currently <85% of their ideal body weight.
• The youth is intellectually incapable of completing the study, e.g. has an intelligence quotient (IQ) < 70.

Key For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which no standard therapy exists, or in the opinion of the Investigator, are not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, or
• Decline standard therapy
• Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
• A RET gene alteration is not required initially. Once adequate PK exposure is achieved, evidence of RET gene alteration in tumor and/or blood is required as identified through molecular assays, as performed for clinical evaluation
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment
• Adequate hematologic, hepatic and renal function
• Life expectancy of at least 3 months For Phase 2: As for phase 1 with the following modifications:
• For Cohort 1: Participants must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy
• Cohorts 1 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Without measurable disease but otherwise meet criteria for Cohorts 1 and 2;
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, or poorly differentiated thyroid cancers with other RET alteration/activation may be allowed with prior Sponsor approval;
• cfDNA positive for a RET gene alteration not known to be present in a tumor sample
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval
• Cohort 7: Participants must have a histologically confirmed stage IB-IIIA NSCLC by AJCC (The American Joint Committee on Cancer) version 8. The tumor must have been deemed resectable by a thoracic surgeon, the participant must be determined to be medically operable based on the determination of a thoracic surgeon, and the participant must not have received prior systemic therapy, including prior radiation therapy, for NSCLC. Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of participants receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Participants are eligible if neurological symptoms and CNS imaging are stable and steroid dose is stable for 14 days prior to the first dose of LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery (SRS)
• Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications

• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12 weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18 years of age) must sign an Ethics or institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study. When appropriate, younger patients will be included in all discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac and pulmonary function to undergo reduced intensity HCT based upon local institutional guidelines, or at a minimum meet requirements noted in eligibility checklist Appendix A-VIII_1. However, significant hepatic and pulmonary dysfunction, if secondary to underlying LCH disease activity, will not exclude patients from protocol enrollment and should be discussed with the National PI Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with ND-CNSLCH irrespective of previous treatments (also those not registered to other Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis). In patients with already established diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion is needed for inclusion into the study
• Stratum VI -- Patients with newly diagnosed SS-LCH and localization other than "multifocal bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as consent for longterm follow-up has not been withheld.
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible for Stratum I, Group 2)

• All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
• Age at diagnosis:
• Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
• Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
• Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or without DS).
• B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment).
• B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).
• Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on a bone marrow (BM) aspirate;
• OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
• OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
• OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
• Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior history of transient myeloproliferative disease (TMD) are not considered to have had a prior malignancy. They would therefore be eligible whether or not the TMD was treated with cytarabine.
• With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1731.
• For patients receiving steroid pretreatment, the following additional exclusion criteria apply:
• Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
• DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV steroids within 4 weeks of diagnosis.
• Patients who have received > 72 hours of hydroxyurea.
• B-ALL patients who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
• Patient must not have acute undifferentiated leukemia (AUL).
• Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be known prior to enrollment).
• Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
• Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).
• For LLy patients, the following additional exclusion criteria apply:
• T-Lymphoblastic Lymphoma.
• Morphologically unclassifiable lymphoma.
• Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
• CNS positive disease or testicular involvement.
• M2 (5%
•25% blasts) or M3 (> 25% blasts) marrow.
• Patients with known Charcot-Marie-Tooth disease.
• Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
• Patients requiring radiation at diagnosis.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating 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.

• Completion of study SOBI003-001
• Informed consent obtained from the patient´s legally authorized representative
• If, in the opinion of the investigator, there are patient specific safety concerns that contraindicates further treatment with SOBI003

• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having localized newly-diagnosed HGG, excluding metastatic disease
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Specimens obtained at the time of diagnostic biopsy must be submitted through APEC14B1 as soon as possible (ASAP), preferably within 13 calendar days of the procedure.
• Patients must be >= 3 years and =< 21 years of age at the time of enrollment
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
• Newly diagnosed high-grade glioma with BRAFV600-mutation
• Positive or negative results for H3 K27M by immunohistochemistry (IHC)
• Histologically confirmed high-grade glioma (World Health Organization [WHO] grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS)
• Patients must have had histologic verification of a high-grade glioma diagnosis. Cerebrospinal fluid (CSF) cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain magnetic resonance imaging (MRI) with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible.
• 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.
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment).
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment).
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or
• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
• Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL)
• Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
• Age 13 to 16 < years (Male 1.5 mg/dL, Female 1.4 mg/dL)
• Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L.
• Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.
• 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 with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
• History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
• Recent myocardial infarction (within the last 6 months);
• Uncontrolled congestive heart failure;
• Unstable angina (within last 6 months);
• Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular [AV] block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment;
• Coronary angioplasty or stenting (within last 6 months);
• Intra-cardiac defibrillators;
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy. Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.

PHASE 1 Key 1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by protocol specified tests. 2. ECOG PS 0-1. 3. Age ≥18 (or age ≥ 20 of age as required by local regulation). 4. Capability to swallow capsules intact (without chewing, crushing, or opening). 5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only measurable disease as defined by RECIST version 1.1 is allowed. 6. Prior cytotoxic chemotherapy is allowed. 7. Prior immunotherapy is allowed. 8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1. 9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria. 10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without supplementation 11. Life expectancy ≥ 3 months. PHASE 2 Key Inclusion Criteria 1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene fusion. 2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either: 1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility. • Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic laboratory for retrospective confirmation by a central diagnostic laboratory test selected by the Sponsor. OR 2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of fusion status by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central diagnostic laboratory for prospective confirmation by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. 4. Age ≥12 (or age ≥ 20 as required by local regulation). 5. Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent or an Assent signed by a parent or legal guardian for subjects age 12 to 17. 6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST (v1.1) are eligible. 7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met. i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv. EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+ solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors 8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria. 9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without supplementation 10. Life expectancy ≥ 3 months. Key Exclusion Criteria PHASE 1 and PHASE 2 1. Concurrent participation in another therapeutic clinical trial. 2. Symptomatic brain metastases or leptomeningeal involvement. 3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the skin, or any in situ carcinoma that has been completely resected, requiring therapy within the previous 2 years. 4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours prior to study entry 5. Clinically significant cardiovascular disease (either active or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2 6. Any of the following cardiac criteria: Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval. 7. Known active infections (bacterial, fungal, viral including HIV positivity). 8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption. 9. Peripheral neuropathy of CTCAE ≥grade 2. 10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior radiation pneumonitis are not excluded.

Key
• Completed study drug treatment in parent study (VX18-445-104); or had study drug interruption(s) in parent study but completed study visits up to the last scheduled visit of the Treatment Period in the parent study Key
• History of study drug intolerance in parent study Other protocol defined Inclusion/Exclusion criteria may apply

Key
• Be at least 12 years of age and weigh at least 40 kg.
• Have Grade 2 oligodendroglioma or astrocytoma per WHO 2016 criteria.
• Have had at least 1 prior surgery for glioma (biopsy, sub-total resection, gross-total resection), with the most recent surgery having occurred at least 1 year (-1 month) and not more than 5 years (+3 months) before the date of randomization, and no other prior anticancer therapy, including chemotherapy and radiotherapy and not be in need of immediate chemotherapy or radiotherapy in the opinion of the Investigator.
• Have confirmed IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) or IDH2 (IDH2 R172K/M/W/S/G mutation variants tested) gene mutation status disease by central laboratory testing during the Prescreening period and available 1p19q status by local testing (eg, fluorescence in situ hybridization [FISH], comparative genomic hybridization [CGH] array, sequencing) using an accredited laboratory.
• Have MRI-evaluable, measurable, non-enhancing disease, as confirmed by the BIRC.
• Have a Karnofsky Performance Scale (KPS) score (for participants ≥16 years of age) or Lansky Play Performance Scale (LPPS) score (for participants <16 years of age) of ≥80%. Key
• Have had any prior anticancer therapy other than surgery (biopsy, sub-total resection, gross-total resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, laser ablation, etc.
• Have features assessed as high-risk by the Investigator, including brainstem involvement either as primary location or by tumor extension, clinically relevant functional or neurocognitive deficits due to the tumor in the opinion of the Investigator (deficits resulting from surgery are allowed), or uncontrolled seizures (defined as persistent seizures interfering with activities of daily life AND failed 3 lines of antiepileptic drug regimens including at least 1 combination regimen).

• All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to enrollment and treatment on AAML1831. Submission of diagnostic specimens must be done according to the Manual of Procedures). Risk stratification will not be possible without the submission of viable samples. Given there are multiple required samples, bone marrow acquisition techniques such as frequent repositioning or performing bilateral bone marrow testing should be considered to avoid insufficient material for required studies. Consider a repeat marrow prior to starting treatment if there is insufficient diagnostic material for the required studies
• Patients must be less than 22 years of age at the time of study enrollment
• Patient must be newly diagnosed with de novo AML according to the 2016 World Health Organization (WHO) classification with or without extramedullary disease
• Patient must have 1 of the following:
• >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)
• In cases where extensive fibrosis may result in a dry tap, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy
• < 20% bone marrow blasts with one or more of the genetic abnormalities (sample obtained within 14 days prior to enrollment)
• A complete blood count (CBC) documenting the presence of at least 1,000/uL (i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells (blasts) if a bone marrow aspirate or biopsy cannot be performed (performed within 7 days prior to enrollment)
• ARM C: Patient must be >= 2 years of age at the time of Late Callback
• ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular Oncology
• ARM C: Patient does not have any congenital long QT syndrome or congenital heart block
• ARM C: Females of reproductive potential must agree to use effective contraception during treatment and for at least 6 months after the last dose of gilteritinib
• ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib and for 2 months after the last dose of gilteritinib
• ARM C: Males of reproductive potential must agree to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib
• ARM D: Patient must be >= 2 years of age at the time of Late Callback
• ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating mutations as reported by Foundation Medicine
• ARM D: Females of reproductive potential must agree to use effective contraception during treatment and for at least 6 months after the last dose of gilteritinib
• ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib and for 2 months after the last dose of gilteritinib
• ARM D: Males of reproductive potential must agree to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib
• NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who transfer to Arm C or Arm D are not eligible
• NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment
• NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking
• NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental retardation)
• NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would prevent computer use or recognition of visual test stimuli
• 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 with myeloid neoplasms with germline predisposition are not eligible
• Fanconi anemia
• Shwachman Diamond syndrome
• Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21
• Any other known bone marrow failure syndrome
• Any concurrent malignancy
• Juvenile myelomonocytic leukemia (JMML)
• Philadelphia chromosome positive AML
• Mixed phenotype acute leukemia
• Acute promyelocytic leukemia
• Acute myeloid leukemia arising from myelodysplasia
• Therapy-related myeloid neoplasms
• Administration of prior anti-cancer therapy except as outlined below:
• Hydroxyurea
• All-trans retinoic acid (ATRA)
• Corticosteroids (any route)
• Intrathecal therapy given at diagnosis
• In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be avoided from the time of enrollment until it is determined whether the patient will receive gilteritinib. Patients receiving gilteritinib will be required to avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the study treatment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• ARM D: Patients with congenital long QT syndrome or congenital heart block are not eligible for this treatment arm

• completion of the EPITOPE study
• Generalized dermatologic disease (for example, active atopic dermatitis, uncontrolled generalized active eczema, ichthyosis vulgaris) extending widely on the skin and especially on the back or arms with no intact zones to apply the Viaskin patches.
• Diagnosis of asthma that evolved to severe, unstable or uncontrolled asthma

• Diagnosis of glucose transporter type 1 deficiency (G1D), confirmed by clinical genotyping at a CLIA-certified laboratory.
• Stable on ketogenic diet at 2.5:1 to 4:1 ratio (i.e., no changes in ratio will have taken place for 2 months). The initiation of a ketogenic diet is previous to
•and thus is not part of this study.
• Males and females 30 months to 35 years and 11 months old inclusive.
• Subjects with evidence of independent, unrelated metabolic and/or genetic disease.
• Subjects with a chronic gastrointestinal disorder, such as irritable bowel syndrome, crohn's disease, or colitis that could increase the subject's risk of developing diarrhea or stomach pain.
• Subjects with a BMI (body mass index) greater than or equal to 30.
• Subjects currently not on ketogenic diet.
• Women who are pregnant or breast feeding may not participate. Women who plan to become pregnant during the course of the study, or who are unwilling to use birth control to prevent pregnancy (including abstinence) may not participate. Females age 10 and over will be asked to provide a urine sample for a pregnancy test via dipstick. Subjects will be asked to agree to abstinence or another form of birth control for the duration of the study.
• Allergy/sensitivity to C7
• Previous use of triheptanoin less than 1 month prior to study initiation.
• Treatment with medium chain triglycerides in the last 24 hours.
• Subjects exhibiting signs of dementia, or diagnosed with any degenerative brain disorder (such as Alzheimer's disease) that would confound assessment of cognitive changes, in the opinion of the investigator.
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of subject or legal guardian/representative to give written informed consent, or assent for children age 10-17,
• Addition of a new antiseizure drug in the previous 3 months.

• Patients must have a body surface area of > 0.3 m^2 at the time of enrollment
• Existing or recurrent desmoid tumor that is deemed not amenable to surgery without significant morbidity and progressed by >= 10% as assessed by RECIST version (v)1.1 within the 6-month period prior to study enrollment
• Patients must have had histologic verification of the desmoid tumor
• Patients must have measurable disease by RECIST v1.1 criteria
• Patient must have received at least one prior course of systemic therapy for desmoid tumor
• Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 50. 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 performance score
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, surgery or radiotherapy prior to entering this study. Patients may not be using or anticipate using these treatments after the observed progression or within the time period stated below
• Cytotoxic chemotherapy: must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea)
• Small molecule tyrosine kinase inhibitors (e.g., sorafenib, pazopanib, imatinib), rapalogs (e.g., temsirolimus, everolimus, sirolimus) or anti estrogen therapy (e.g., tamoxifen): may not have received within 28 days prior to the first dose of study treatment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent
• Local regional tumor directed therapy, including, but not limited to small port radiation therapy (RT), radiofrequency ablation, cryotherapy, surgery: at least 2 weeks since these therapies and all toxicity must have resolved to grade =< 1. If prior craniospinal RT or if >= 50% radiation of pelvis then >= 6 months must have elapsed. If other substantial bone marrow (BM) radiation, then >= 6 weeks must have elapsed
• Stem cell transplant (SCT): No evidence of active graft versus (vs.) host disease. For allogeneic SCT, >= 6 months must have elapsed
• No prior gamma-secretase, Notch or beta-catenin inhibitor
• Investigational drugs: must not have received investigational drug within 4 weeks of study entry, and all toxicities related to prior therapy must be resolved to grade =< 1 or baseline
• Concomitant Medication Restrictions
• Steroids: patients who are receiving dexamethasone must be on a stable or tapering dose for at least 2 weeks prior to study entry. Use of steroids for non-tumor indications (e.g., asthma or severe allergic reaction) is permitted
• Growth factor(s): must not have received within 1 week of entry onto this study
• Patients who are currently receiving drugs that are strong inducers or moderate to strong inhibitors of CYP3A4 are not eligible. Strong inducers or moderate to strong inhibitors of CYP3A4 are not allowed from 14 days prior to enrollment to the end of protocol therapy. Note: CYP3A4 inducing anti-epileptic drugs on a stable dose, are allowed
• Must not be receiving non-steroidal anti-inflammatory drugs (NSAIDs) as treatment for desmoid tumor after the observed progression and patient agrees to not use NSAIDs while on study. Occasional use (defined as =< 3 times per week) for treatment of pain is permitted
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)
• Hemoglobin >= 9.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment)
• 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 (within 7 days prior to enrollment):
• Age: Maximum serum creatinine (mg/dL)
• Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male and female)
• Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male and female)
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male and female)
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male and female)
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (unless secondary to previously diagnosed Gilbert's syndrome) (within 7 days prior to enrollment)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L (within 7 days prior to enrollment)
• Adequate cardiac function defined as:
• Corrected QT (QTc) interval < 470 ms
• No history of congenital or acquired prolonged QTc syndrome
• No history of clinically significant cardiac arrhythmias, congestive heart failure, stroke or myocardial infarction within 6 months prior to study entry
• 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
• Active or chronic infection within 7 days prior to study entry
• Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication, prior surgical procedures affecting absorption (e.g., gastric bypass), malabsorption syndrome, and active peptic ulcer disease)
• Patients with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction
• Known active infection with hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
• Patients with a prior history of malignancy, with the exceptions of desmoid tumor(s) and non-melanoma skin cancer, who are not in remission for more than 3 years
• Patients who are unable to swallow tablets. Tablets must not be crushed or chewed. Administration of nirogacestat via gastrostomy tube or nasogastric tube is not allowed
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study
• Sexually active female patients of reproductive potential who have not agreed to use 1 method of highly effective contraceptive (including copper-containing intrauterine device, condom with spermicidal foam/gel/film/cream/suppository, bilateral tubal ligation, established use of inserted, injected or implanted hormonal method of contraception, abstinence, or male sterilization) for the duration of their study participation and for at least 6 months after last dose of nirogacestat. A second form of contraception (i.e. barrier method) is required for patients who are using hormonal contraception as nirogacestat may reduce the efficacy of hormonal contraceptives
• Sexually active male patients of reproductive potential who have not agreed to use a condom and their female partner who have not agreed to use one of the highly effective methods of contraception mentioned above during treatment and for at least 90 days after the last dose of nirogacestat
• Female patients who are breastfeeding
• Female patients who are pregnant. These patients are excluded because there is no available information regarding the effects of nirogacestat on the developing human fetus and inhibition of gamma-secretase is known to be teratogenic
• Female patients of childbearing potential unless a negative pregnancy test result has been obtained

Pre-operative: 1. Less than 18 years of age. 2. Requires an elective (non-emergent), open (non-laparoscopic), pelvic, abdominal, or thoracic (non-cardiac) surgical procedure. 3. Subject and/or subject's legal guardian is willing to give permission for the subject to participate in the clinical trial and provide written informed consent for the subject. In addition, assent must be obtained from pediatric subjects who possess the intellectual and emotional ability to comprehend the concepts involved in the clinical trial. Intra-operative: 4. Presence of an appropriate (as defined in inclusion criterion 5) parenchymous or soft tissue TBS identified intra-operatively by the investigator (the surgeon). 5. TBS has Grade 1 (mild) or Grade 2 (moderate) bleeding intensity according to the investigator's (the surgeon's) judgment. The intensity of the bleeding at the TBS will be rated by the investigator using the 5-point validated bleeding severity scale. Pre-operative: 1. Admitted for trauma surgery. 2. Unwilling to receive blood products. 3. Known history of severe (eg, anaphylactic) reaction to blood products. 4. Known history of intolerance to any of the components of the investigational product (IP). 5. Female subjects who are pregnant, breastfeeding or, if of child-bearing potential (ie, adolescent), unwilling to practice a highly effective method of contraception. 6. Previously enrolled in a clinical trial with FS Grifols. 7. Currently participating, or during the study is planned to participate, in any other investigational device or medicinal product study without prior and explicit approval from the sponsor. Intra-operative: 8. An appropriate parenchymous or soft tissue TBS (as defined in exclusion criteria 9 and 10) cannot be identified intra-operatively by the investigator (the surgeon). 9. TBS has Grade 3 (severe) bleeding according to the investigator's (the surgeon's) judgment that cannot be controlled with conventional surgical techniques to Grade 1 or Grade 2 bleeding. The intensity of the bleeding at the TBS will be rated by the investigator using the 5-point validated bleeding severity scale. 10. TBS is in an actively infected surgical field. 11. Occurrence of major intra-operative complications that require resuscitation or deviation from the planned surgical procedure. 12. Application of any topical hemostatic agent on the resection surface of parenchyma or soft tissue prior to application of the IP.

• Patients must be:
• < 12 months (< 365 days) of age at diagnosis with INRG stage L1; or
• < 18 months (< 547 days) of age at diagnosis with INRG stage L2 or stage Ms neuroblastoma/ganglioneuroblastoma
• Enrollment on ANBL00B1 or APEC14B1 is required for all newly diagnosed patients
• Patients must have newly diagnosed v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) non-amplified neuroblastoma (International Classification of Diseases for Oncology [ICD-O] morphology 9500/3) or MYCN non-amplified ganglioneuroblastoma verified by histology
• Patients must meet the specified criteria for one of the treatment groups defined below; genomic features include MYCN gene amplification, segmental chromosome aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p, or 17q) and deoxyribonucleic acid (DNA) index
• "Favorable" genomic features are defined by one or more whole-chromosome gains or hyperdiploid tumor (DNA index > 1) in the absence of segmental chromosome aberrations as defined above
• "Unfavorable" genomic features are defined by the presence of any segmental chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q or somatic copy number gain at 1q, 2p, or 17q) or diploid tumor (DNA index = 1); this includes copy neutral loss of heterozygosity (LOH)
• Only patients with MYCN non-amplified tumors are eligible for this study
• Group A: patients < 12 months (< 365 days) of age with newly diagnosed INRG stage L1 neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• Greatest tumor diameter < 5 cm of adrenal or non-adrenal origin
• Patients with non-adrenal primaries are eligible, but must have positive uptake on metaiodobenzylguanidine (MIBG) scan or elevated catecholamine metabolites (urine or serum) to support the diagnosis of neuroblastoma
• No prior tumor resection or biopsy
• Group A will be further split into two subsets, which are mutually exclusive, for statistical purposes
• Group A1:
• > 6 months and < 12 months of age with an adrenal primary tumor < 5 cm in greatest diameter OR
• Patients less than 6 months of age with an adrenal primary tumor > 3.1 and < 5 cm in greatest diameter OR
• < 12 months of age with a non-adrenal primary site < 5 cm in greatest diameter
• Group A2: =< 6 months of age with an adrenal primary site and tumor =< 3.1 cm in greatest diameter.
• Group B: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage L2 neuroblastoma/ganglioneuroblastoma who meet the following criteria:
• No life threatening symptoms or no impending neurologic or other organ function compromise (e.g. epidural or intraspinal tumors with existing or impending neurologic impairment, periorbital or calvarial-based lesions with existing or impending cranial nerve impairment, anatomic or mechanical compromise of critical organ function by tumor [abdominal compartment syndrome, urinary obstruction, etc.]); horner syndrome is not considered neurologic compromise
• No prior tumor resection, tumor biopsy ONLY
• Only patients with both favorable histology and favorable genomic features will remain on study as part of Group B; the institution will be notified of histologic and genomic results within 3 weeks of specimen submission on ANBL00B1 or APEC14B1
• Group C: patients < 18 months (< 547 days) of age with newly diagnosed INRG stage Ms neuroblastoma/ganglioneuroblastoma
• No prior radiotherapy or chemotherapy, with the exception of dexamethasone, which is allowed
• 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 with MYCN amplified tumors are not eligible
• Group B and C patients who do not enroll on ANBL1232 within 4 weeks of definitive diagnostic procedure
• Group A and C patients, not required to undergo tumor biopsy, who do not enroll on ANBL1232 within 4 weeks of confirmatory imaging study

• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line therapy without having achieved a prior partial or complete remission OR Biopsy proven residual disease at the completion of planned standard initial front-line therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or complete remission
• Newly diagnosed high risk disease, defined as having an expected event free survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for profiling from diagnosis or progression / recurrence --- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started matched targeted therapy based on the report .
• No Therapy Planned -- Patients who have declined further anticancer therapy will be excluded.
• Performance Status -- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be excluded.

INCLUSION CRITERIA
• Medulloblastoma or medulloblastoma variants including posterior fossa PNET as documented by an institutional pathologist.
• Participant's age meets one of the following: (1) Age greater than or equal to 3 years and less than 22 years of age at the time of diagnosis (may enroll on Strata W, S or N), OR (2) age is greater than or equal to 22 years and less than 40 years AND patient has SHH medulloblastoma (must enroll on Stratum S).
• No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery.
• Patients must begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes second surgeries to resect residual tumor).
• Adequate performance status: children < 10-Lansky Score ≥ 30; children ≥ 10-Karnofsky ≥ 30 (except for posterior fossa syndrome).
• Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants > 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment.
• Biological parent(s) of participant (child) enrolling on this protocol. These parents will be assigned to cohort P. The exclusion criteria below do not apply to this cohort. EXCLUSION CRITERIA
• CNS embryonal tumor other than medulloblastoma or PNET in the posterior fossa, for example, patients with diagnosis of Atypical Teratoid / Rhabdoid Tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, ETANTR are excluded.
• Research participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results history. Participants in the Stratum S maintenance chemotherapy portion of the study must meet the criteria below prior to start of vismodegib therapy:
• Participants must be Stratum S (SHH)
• Participants must be skeletally mature defined as females with a bone age ≥ 15 years and males with a bone age ≥ 17 years.
• Must be able to swallow pills
• BSA must be >0.67 and <2.5 m2
• Male and female participants of reproductive potential must agree to effective contraception during and after study treatment. See Appendices I and II for further guidance for participants receiving vismodegib
• ANC ≥ 1000/mm^3 (after G-CSF discontinued)
• Platelets ≥ 50,000/mm^3 (without support)
• Hgb ≥ 8 g/dL (with or without transfusion support)
• Serum creatinine ≤ 1.5 mg/dL
• Total bilirubin ≤ 1.5X the institutional ULN
• SGPT (ALT) ≤ 2.5X the institutional ULN
• SGOT (AST) ≤ 2.5X the institutional ULN
• Alkaline Phosphatase ≤ 1.5X the institutional ULN
• Serum albumin ≥ 2.5 g/dL Participants in the exercise intervention portion of the study must meet all criteria below:
• Must be ≥ 5 years and < 22 years at the time of enrollment
• Must have no congenital heart disease
• Must be capable of performing the exercise intervention at the time of baseline assessment as determined by the treating physician. Participants in the cognitive remediation intervention portion of the study must meet all criteria below:
• Completed protocol-directed radiation therapy
• ≥5 years at the time of remediation intervention consent or age is greater than or equal to 22 years and less than 40 years and patient has SHH medulloblastoma
• English as primary language and training aide who speaks English available to participate in required sessions
• No significant cognitive impairment operationalized as either an IQ < 70 for children with St. Jude SJMB12 study baseline testing or based on clinician judgment baseline IQ missing
• No major sensory or motor impairment that would preclude valid cognitive testing (e.g., unresolved posterior fossa syndrome, blindness, poorly controlled seizures/photosensitive epilepsy, psychosis) or a major psychological condition that would preclude completion of the intervention (e.g., significant oppositionality, autism spectrum disorder, severe anxiety or depressive symptoms)

1. Between 15 and 49 years of age, inclusive, at Visit 1. 2. Anti-nuclear antibody (ANA) titer of 1:80, or greater, as determined by immunofluorescence assay (IFA). 3. Participants must have at least one (but not three or more) additional clinical or laboratory criterion from the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. 4. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study. 1. The subject meets the 2012 SLICC classification criteria for SLE at Visit 1 (i.e., ANA plus 3 other criteria, or ANA plus biopsy-proven lupus nephritis). 2. The subject has been diagnosed with another autoimmune disorder, other than autoimmune thyroid conditions. 3. The subject has fibromyalgia, based on clinical history and exam. 4. The subject has previously been or is currently being treated with oral antimalarial agents including hydroxychloroquine, chloroquine, or quinacrine. 5. The subject is currently or has been treated with immunosuppressive, immune modifying, or cytotoxic medications as listed in Section 7.2. 6. Use of any investigational agent within the preceding 12 months. 7. History of primary immunodeficiency. 8. Active bacterial, viral, fungal, or opportunistic infection. 9. Evidence of infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C. 10. Concomitant malignancy or history of malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. 11. The subject has significant findings on ophthalmological examination that, in the opinion of the examining Ophthalmologist, prevent safe use of hydroxychloroquine. 12. The subject has other contraindications to treatment with hydroxychloroquine including pre-existing ocular disease, hepatic impairment, psoriasis, porphyria, or allergy to the drug or class. 13. Co-morbidities requiring systemic corticosteroid therapy greater than 10 mg of prednisone per day, or equivalent, or a change in corticosteroid dose within the 3 months prior to Visit 1. 14. Starting, stopping, or changing the dose of over the counter or prescription non-steroidal anti-inflammatory drugs (NSAIDs) in the three months prior to Visit 1. 15. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. 16. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. 17. Inability to comply with the study visit schedule and procedures.

• Patient must be newly diagnosed or relapsed/progressed with a brain tumor that has not previously been treated with CRT
• Note: COG therapeutic study participation is not required for ACCL10P1 enrollment
• Patient enrollment must occur within 4 calendar months following completion of CRT
• Reminder: after patient enrollment, baseline testing followed by randomization must occur within 2-4 months after completion of CRT
• The patient must have an identified caregiver who is willing and able to oversee the training practice during the intervention period (ie, for 5-9 weeks starting approximately 3 months after completion of CRT)
• The patient must have access to a telephone and phone number where they can be reached
• The patient and caregiver must have reading, speaking and listening comprehension of English
• All patients and/or their parents or legal guardians must sign a written informed consent (patient assent is also recommended when applicable according to each institution's policy)
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
• Patients with pontine glioma are not eligible
• Patients with an estimated survival of less than one year are not eligible
• Patients with a history of traumatic brain injury prior to tumor diagnosis are not eligible
• Patients with a motor, visual, or auditory handicap that prevents computer use (e.g., unresolved posterior fossa syndrome) are not eligible to participate in this trial
• Patients with full-scale intelligence quotient (IQ) < 70 per previous testing OR existing diagnosis of/educational classification as a student with an intellectual disability are not eligible

Inclusion criteria: Patients with Pompe disease who previously completed a neoGAA study. The patient and/or their parent/legal guardian is willing and able to provide signed informed consent, and the patient, if <18 years of age, is willing to provide assent if deemed able to do so. The patient (and patient's legal guardian if patient is <18 years of age) must have the ability to comply with the clinical protocol. The patient, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin] at baseline. Exclusion criteria: The patient is concurrently participating in another clinical study using investigational treatment. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study. The patient has clinically significant organic disease (with the exception of symptoms relating to Pompe disease), including clinically significant cardiovascular, hepatic, pulmonary, neurologic, or renal disease, or other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, precludes participation in the study or potentially decreases survival. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.