1. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative. 2. Willingness and ability to adhere to the study visit schedule and other protocol requirements. 3. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria: 1. Sweat chloride equal to or greater than 60 mEq/liter by quantitative pilocarpine iontophoresis test 2. Two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 4. Phase 1 only: Age 6 to 18 years, inclusive, at the time of consent. 5. Phase 2 only: Ages 9 to 18 years, inclusive, at the time of consent. 6. Clinically stable with no acute antibiotic usage in the 14 days prior to the first visit. 7. Genotype with F508del on at least one allele. 8. No change in chronic pulmonary medications or therapies in the 28 days prior to the first visit. 9. Stable CFTR modulator therapy (TEZ/IVA or LUM/IVA) for at least 28 days prior to the first visit or currently not receiving CFTR modulator therapy. 10. Ability to cooperate with MRI procedures. 11. Phase 1 only: FEV1 greater than or equal to 80% predicted based on GLI reference equations. 1. Standard MRI exclusions (Metal implants, claustrophobia). 2. For females of childbearing potential: Positive urine pregnancy test at Screening or Visit 1 or Lactating. 3. Any other condition that, in the opinion of the Site Investigator/designee, would preclude informed consent or assent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

• Any participant with SMA who received onasemnogene abeparvovec-xioi gene replacement therapy in an Novartis Gene Therapies, Inc. sponsored clinical study
• Participant/parent/legal guardian willing and able to complete the informed consent process and comply with study procedures and visit schedule
• Parent/legal guardian unable or unwilling to participate in the long-term follow-up safety study

1. Participant is < 21 years of age 2. Parent/ Legal Guardian/ Adult Participant can understand the consent process and is willing to provide informed consent/HIPAA: 3. (a) Participant is receiving one or more of the study drugs of interest at the time of enrollment or (b) Participant is NOT receiving one or more of the study drugs of interest but is SARS-COV-2 positive within 60 days prior to enrollment 1. Participant has a known pregnancy Below exclusion criteria apply only to participants receiving one or more of the study drugs of interest at the time of enrollment, 2. Has had intermittent dialysis within previous 24 hours 3. Has had a kidney transplant within previous 30 days 4. Has had a liver transplant within previous 1 year 5. Has had a stem cell transplant within previous 1 year 6. Has had therapeutic hypothermia within previous 24 hours 7. Has had plasmapheresis within the previous 24 hours 8. Has a Ventricular Assist Device 9. Has any condition which would make the participant, in the opinion of the investigator, unsuitable for the study

1. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative 2. Enrolled in the CFFPR 3. Male or female ≥ 4 months of age on day of study visit 4. Diagnosis of CF. 5. Current treatment with a prescribed commercially approved CFTR modulator for at least 90 days prior to enrollment 6. Able to perform the testing and procedures required for this study, as judged by the investigator Additional Inclusion Criteria for CHEC-PKPD Sub-Study: 1. Male or female ≥ 6 years of age on day of study visit. 2. Current treatment with elexacaftor/tezacaftor/ivacaftor for at least 90 days prior to enrollment. 3. Last dose of elexacaftor/tezacaftor/ivacaftor taken at least 24hours and last dose of ivacaftor taken at least 12 hours prior to trough blood draw on day of visit. 1. 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 2. Currently enrolled in an investigational trial (including open-label follow-on studies and Early Access Programs (EAP) of an agent expected to have an impact on sweat chloride (refer to current list provided on study website)

Ivacaftor Arm: Subjects From Study 124 (NCT02725567 ) Part B:
• Subjects transitioning from Study 124 Part B must have completed the last study visit of Study 124 Part B.
• As judged by the investigator, parent or legal guardian must be able to understand protocol requirements, restrictions, and instructions; and must sign the informed consent form (ICF). Ivacaftor Arm: Subjects Not From Study 124 Part B:
• Confirmed diagnosis of CF, or 2 CF-causing mutations.
• An ivacaftor- responsive CFTR mutation on at least 1 allele. Subjects will be eligible in countries/regions where ivacaftor is approved for use in subjects 2 years of age and older.
• As judged by the investigator, parent or legal guardian must be able to understand protocol requirements, restrictions, and instructions; and must sign the ICF. Observational Arm:
• Received ivacaftor treatment in Study 124 Part B and elected not to enroll or ineligible to enroll in the ivacaftor arm of Study 126. Ivacaftor Arm: Subjects From Study 124 Part B:
• History of any illness or condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering ivacaftor to the subject.
• Subjects receiving commercially available ivacaftor treatment Ivacaftor Arm: Subjects Not From Study 124 Part B:
• History of any illness or condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering ivacaftor to the subject
• An acute upper or lower respiratory infection, or pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1
• Abnormal liver function at screening
• Hemoglobin <9.5 g/dL at screening
• History of solid organ or hematological transplantation
• Use of any moderate or strong inducers or inhibitors of CYP3A within 2 weeks of Day 1 Observational Arm:
• Receiving ivacaftor treatment Other protocol defined Inclusion/Exclusion criteria may apply.

• 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 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.
• 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 within 1 week (7 days) prior to the start of systemic protocol therapy.
• 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.

• Enrollment must occur within 6 months of initial disease presentation OR within 6 months of refractory disease, disease progression, disease recurrence, second or secondary malignancy, or post-mortem
• Patients previously enrolled on ACCRN07 are eligible to enroll on Tracking Outcome, Registry and Future Contact components of APEC14B1 any time after they reach age of majority
• Patients with a known or suspected neoplasm that occurs in the pediatric, adolescent or young adult populations are eligible for enrollment as follows:
• All cancer cases with an International Classification of Diseases for Oncology (ICD-O) histologic behavior code of two "2" (carcinoma in situ) or three "3" (malignant)
• All neoplastic lesions of the central nervous system regardless of behavior, i.e., benign, borderline or malignant
• The following other benign/borderline conditions:
• Mesoblastic nephroma
• Teratomas (mature and immature types)
• Myeloproliferative diseases including transient myeloproliferative disease
• Langerhans cell histiocytosis
• Lymphoproliferative diseases
• Desmoid tumors
• Gonadal stromal cell tumors
• Subjects must be =< 25 years of age at time of original diagnosis, except for patients who are being screened specifically for eligibility onto a COG (or COG participating National Clinical Trials Network [NCTN]) therapeutic study, for which there is a higher upper age limit
• All patients or their parents or legally authorized representatives must sign a written informed consent and agree to participate in at least one component of the study; parents will be asked to sign a separate consent for their own biospecimen submission
• If patients or their parents or legally authorized representatives have not signed the Part A subject consent form at the time of a diagnostic bone marrow procedure, it is recommended that they initially provide consent for drawing extra bone marrow using the Consent for Collection of Additional Bone Marrow; consent using the Part A subject consent form must be provided prior to any other procedures for eligibility screening or banking under APEC14B1

• Patients with the first occurrence of any tumor of the kidney identified on CT scan or MRI are eligible for this study; histologic diagnosis is not required prior to enrollment but is required for all patients once on study
• Eligible tumors include (but are not limited to):
• Nephroblastic tumors
• Nephroblastoma (Wilms' tumor) (favorable histology, anaplasia [diffuse, focal])
• Nephrogenic rests and nephroblastomatosis
• Cystic nephroma and cystic partially differentiated nephroblastoma
• Metanephric tumors (metanephric adenoma, metanephric adenofibroma, metanephric stromal tumor)
• Mesoblastic nephroma (cellular, classic, mixed)
• Clear cell sarcoma
• Rhabdoid tumor (any malignant rhabdoid tumor occurring outside the central nervous system [CNS])
• Renal epithelioid tumors of childhood (papillary renal cell carcinoma, medullary renal cell carcinoma, renal tumors associated with Xp11.2 translocations, oncocytic renal neoplasms after neuroblastoma)
• Angiolipoma
• Ossifying renal tumor of infancy
• Patients with the first occurrence of the following tumors are also eligible:
• Extrarenal nephroblastoma or extrarenal neprogenic rests
• Malignant rhabdoid tumor occurring anywhere outside the central nervous system
• Required specimens, reports, forms, and copies of imaging studies must be available or will become available for submission and the institution must intend on submitting them as described in the protocol procedures
• For ALL patients, (with exception of bilateral, bilaterally predisposed, multicentric, or unilateral tumor in solitary kidney planning to enroll without biopsy***), the following submissions are required:
• A complete set of recut hematoxylin and eosin (H & E) slides (including from sampled lymph nodes, if patient had upfront nephrectomy)
• * Tissue must be from diagnosis, prior to any renal tumor directed chemotherapy or radiation (only exception is for presumed favorable histology Wilms tumor [FHWT] patients discovered to have diffuse anaplastic Wilms tumor [DAWT] at delayed nephrectomy and plan to enroll at delayed nephrectomy)
• Representative formalin-fixed paraffin-embedded tissue block or if a block is unavailable, 10 unstained slides from a representative block of tumor, if available.
• Tissue must be from diagnosis, prior to any renal tumor directed chemotherapy or radiation (only exception is for presumed FHWT patients discovered to have DAWT at delayed nephrectomy and plan to enroll at delayed nephrectomy)
• Institutional pathology report, Specimen Transmittal Form, and Pre-Treatment Pathology Checklist
• Copies of images and institutional reports of CT and/or MRI abdomen and pelvis, and Pre Treatment Imaging Checklist
• Copies of images and institutional report of chest CT for all malignant tumors
• Institutional surgical report(s) and Pre-Treatment Surgical Checklist
• CRFs: Staging Checklist and Metastatic Disease Form (if metastatic disease is noted on imaging)
• Patients with bilateral, bilaterally predisposed, multicentric, or unilateral tumor in solitary kidney planning to enroll without biopsy via imaging only
•these patients will not have central review or have a risk assignment issued, but may contribute to specimen banking for future research. However, if biopsy is done, tissue must be submitted as for other renal tumors, and initial risk assignment will require pathology and surgical rapid central reviews. The Specimen Transmittal Form and Pre Treatment Pathology Checklist are also needed.
• Please note: if the above required items are not received within 120 days of study enrollment, the patient will be considered off study
• 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

• Bone marrow hypocellular for age
• Moderate or severe aplastic anemia defined by one of the following: peripheral blood neutrophils < 0.5 x 10^9/L; platelets < 30 x 10^9/L or platelet transfusion dependence; reticulocytes < 50 x 10^9/L in anemic patients or red cell transfusion dependence
• Diagnosis of dyskeratosis congenita based on clinical triad of abnormalities of skin pigmentation, nail dystrophy, oral leukoplakia; OR one of clinical triad and presence of two or more associated features; OR a pathogenic mutation in DKC1,TERC, TERT, NOP10, NHP2, TCAB1, TINF2, CTC1, PARN, RTEL1, ACD, NAF1, STN1, or ZCCHC8, as reported by a CLIA-approved laboratory; OR age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes as reported by a CLIA-approved laboratory; OR Hoyeraal-Hreidarsson syndrome; OR Revesz syndrome
• Availability of a related or unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1.
• Patient and/or legal guardian must be able to sign informed consent.
• Donor must provide a marrow allograft.
• Diagnosis of Fanconi anemia must be excluded by mitomycin C or diepoxybutane chromosomal breakage testing on peripheral blood at a CLIA-approved laboratory (not required for patients with a genetic mutation consistent with DC)
• Adequate renal function with glomerular filtration rate equal to or greater than 30 ml/min/1.73 m2
• Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination.
• Karnofsky/Lansky performance status < 40.
• Uncontrolled bacterial, viral or fungal infections.
• Positive test for the human immunodeficiency virus (HIV).
• Pregnancy or breastfeeding.
• Known severe or life-threatening allergy or intolerance to fludarabine, alemtuzumab, mycophenolate mofetil or both cyclosporine and tacrolimus.
• Positive patient anti-donor HLA antibody, which is deemed clinically significant.
• Prior allogeneic marrow or stem cell transplantation.
• Prior solid organ transplantation.

• Willing and able to provide informed consent or, in the case of patients under the age of 18 years (or 16 years, depending on the region), provide assent (if required) and informed consent by a legally authorized representative after the nature of the study has been explained, and prior to any research-related procedures.
• Clinical diagnosis of XLH based on family history, OR confirmed PHEX mutation, OR biochemical profile consistent with XLH.
• Willing and able to comply with the study visit schedule and study procedures.
• Concurrent enrollment in an Ultragenyx-sponsored clinical trial is NOT permitted.
• Serious medical or psychiatric comorbidity.
• Less than one year of life expectancy.

Inclusion Criterion:
• Patient treated for esophageal atresia with Flourish device starting May 12, 2017

• Confirmed diagnosis of CF by sweat chloride value or CF mutation criteria.
• Have 1 of the following 10 CFTR mutations on at least 1 allele: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D or R117H (eligible in regions where ivacaftor is approved for use). Part A/B group may also have other ivacaftor-responsive mutations.
• Hematology, serum chemistry, and vital signs results at screening with no clinically significant abnormalities that would interfere with the study assessments, as judged by the investigator.
• History of any illness or condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject
• Colonization with organisms associated with a more rapid decline in pulmonary status at screening (Only for Parts A and B)
• History of abnormal liver function or abnormal liver function at screening
• History of solid organ or hematological transplantation
• Use of any moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 3A within 2 weeks before Day 1
• Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives before screening
• Hemoglobin (Hgb) <9.5 g/dL at screening
• Chronic kidney disease of Stage 3 or above
• Presence of a non-congenital or progressive lens opacity or cataract at Screening Other protocol defined Inclusion/Exclusion Criteria may apply.

• Diagnosis of CF.
• Age ≥ 12 years at the Screening Visit.
• Forced expiratory volume in 1 second (FEV1) ≥ 70 % predicted at the Screening Visit if < 18 years old, and ≥ 60 % predicted at Screening Visit if ≥ 18 years old.
• Clinically stable with no significant changes in health status within the 7 days prior to and including the Screening Visit.
• Current treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for at least the 90 days prior to and including the Screening Visit and willing to continue daily use for the duration of the study.
• Currently taking hypertonic saline (at least 3%) and/or dornase alfa for at least the 90 days prior to and including the Screening Visit and willing to continue daily use for the 2-week screening period.
• Active smoking or vaping.
• Use of an investigational drug within 28 days prior to and including the Screening Visit.
• Changes to chronic therapy (e.g., ibuprofen, azithromycin, inhaled tobramycin, aztreonam lysine) within 28 days prior to and including the Screening Visit. This includes new airway clearance routines.
• Acute use of antibiotics (oral, inhaled or IV) or acute use of systemic corticosteroids for respiratory tract symptoms within 7 days prior to and including the Screening Visit.
• Chronic use of systemic corticosteroids at a dose equivalent to ≥ 10mg per day of prednisone within 28 days prior to and including the Screening Visit.
• Antibiotic treatment for nontuberculous mycobacteria (NTM) within 28 days prior to and including the Screening Visit.

• Part A:
• Less than 5 years of age at the first study visit.
• Documentation of a CF diagnosis. Part B:
• Participated in Part A OR less than 6 years of age at the first study visit.
• Documentation of a CF diagnosis.
• CFTR mutations consistent with FDA labeled indication of highly effective modulator therapy (ivacaftor or elexacaftor/tezacaftor/ivacaftor).
• Physician intent to prescribe ivacaftor or elexacaftor/tezacaftor/ivacaftor.
• Part A and Part B: Use of an investigational drug within 28 days prior to and including the first study visit. Use of ivacaftor or elexacaftor/tezacaftor/ivacaftor within the 180 days prior to and including the first study visit. Use of chronic oral corticosteroids within the 28 days prior to and including the first study visit.

Key
• Subjects From Study VX16-809-122 Part B (Study 122)
• Completed the 24-week Treatment Period and the Safety Follow-up Visit in Study 122B
• Subjects Not From Study 122
• Subjects will be 1 to less than 2 years of age
• Homozygous for the F508del mutation (F/F) Key
• Any clinically significant laboratory abnormalities 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.

• The applicant has a condition that remains undiagnosed despite thorough evaluation by healthcare providers (including clinical genetic testing).
• The applicant has at least one objective finding that is likely to have an identifiable genetic etiology.
• The applicant likely has a currently undescribed/new genetic condition or a known genetic condition associated with a novel gene.
• The applicant/legal guardian agrees to the collection, storage and recurrent sharing of coded information and biomaterials for research and diagnostic purposes both within and outside of the University of Wisconsin-Undiagnosed Diseases Program (UW-UDP)
• The applicant/legal guardian agrees to receive secondary findings from genetic testing.
• The applicant/legal guardian has sufficient proficiency in English to understand the consent.
• The applicant already has a diagnosis that explains the objective findings.
• A specific diagnosis is suspected and a standard clinical workup performed by the referring/primary care provider would be appropriate.
• The UW-UDP is unlikely to improve on the comprehensive workup the applicant has already received.
• The applicant's symptoms are likely multifactorial or due to a non-genetic cause.

• Pre-registration Eligibility Criteria (Step 0)
• Submission of bone marrow aspirate and peripheral blood for MRD analysis is mandatory prior to registration; the bone marrow sample should be from the first aspiration (i.e. first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be initiated as soon as possible after pre-registration. The specimens should be sent to the HEME Biobank.
• Lumbar Puncture (Spinal Tap) and Intrathecal Methotrexate:
• Patients may receive the day 1 of course IA dose of intrathecal (IT) methotrexate during the prior-to-registration lumbar puncture (or the venous line placement) to avoid a second lumbar puncture. If the dose is administered prior to registration, then systemic chemotherapy must begin within 7 days of this IT chemotherapy.
• Registration Eligibility Criteria (Step 1)
• Morphologic diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) based on World Health Organization (WHO) criteria. Patients with Burkitt lymphoma/leukemia are not eligible.
• CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts by local hematopathology evaluation.
• Philadelphia chromosome/BCR-ABL1-negative ALL by cytogenetics, fluorescence in situ hybridization (FISH), and/or polymerase chain reaction (PCR). If any test is positive for Philadelphia chromosome/BCR-ABL1, then the patient is ineligible.
• No active central nervous system (CNS) leukemia (i.e. only CNS-1 disease allowed). Active CNS leukemia is defined as morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within 28 days prior to registration, symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurological dysfunction) within the 28 days prior to registration, and/or known asymptomatic parenchymal CNS mass lesions; see below for additional guidance. Prophylactic intrathecal medication alone is not an exclusion.
• Categories of CNS Involvement for CNS Evaluation Prior to Registration:
• CNS 1: CSF has < 5 WBC/uL with cytospin negative for blasts; or >= 10 red blood cell (RBC)/uL with cytospin negative for blasts.
• CNS 2: CSF has < 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, WBC/uL >= 5 but less than Steinherz/Bleyer algorithm with cytospin positive for blasts (see below).
• CNS 3: CSF has >= 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, >= 5 WBC/uL and positive by Steinherz/Bleyer algorithm (see below); or clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome). Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar Punctures:
• If the patient has leukemia cells in the peripheral blood and the lumbar puncture is traumatic and contains >= 5 WBC/uL with blasts, the following algorithm should be used to define CNS disease: CSF WBC/CSF RBC > 2 x (Blood WBC/Blood RBC count)
• Patients with known or suspected testicular involvement by leukemia are allowed provided that the patient receives concomitant scrotal/testicular radiotherapy.
• Unilateral or bilateral testicular enlargement should be assessed by ultrasound or other imaging technique. Biopsy is recommended if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic mass, but further assessments are per treating physician discretion.
• Not pregnant and not nursing.
• This study involves agents that have known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required.
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
• No unstable cardiac disease such as myocardial infarction, angina pectoris, uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months of registration.
• No impaired cardiac function, defined as left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) stage III or IV congestive heart failure (CHF).
• Patients with known human immunodeficiency virus (HIV) infection are eligible if they have been on effective antiretroviral therapy with an undetectable viral load tested within 6 months of registration.
• Patients with hepatitis B virus (HBV) are eligible only if they meet all the following:
• On HBV-suppressive therapy.
• No evidence of active virus.
• No evidence of HBV-related liver damage.
• Patients with hepatitis C virus (HCV) are eligible only if they meet all the following:
• Successfully completed complete-eradication therapy with undetectable viral load.
• No evidence of HCV-related liver damage.
• No history of clinically relevant neurologic disorder such as epilepsy, seizure, aphasia, stroke, severe brain injury, structural brain abnormality, benign brain tumor, dementia, Parkinson's disease, movement disorder, cerebellar disease, or other significant CNS abnormalities.
• No prior additional malignancy (i.e. in addition to ALL) except adequately treated basal- or squamous-cell skin cancer, in situ cervical cancer, stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for >= 2 years.
• No history of clinically significant ventricular arrhythmia, unexplained non-vasovagal syncope, or chronic bradycardic states such as sinoatrial block or higher degree of atrioventricular block unless a permanent pacemaker has been implanted.
• No history of chronic liver disease, including cirrhosis.
• No history of sinusoidal occlusion syndrome/veno-occlusive disease of the liver.
• No uncontrolled infection or recent history (within 4 months prior to registration) of deep tissue infections such as fasciitis or osteomyelitis.
• Total bilirubin, serum =< 1.5 x upper limit of normal (ULN)*
• Except in the event of: 1) Gilbert disease, in which case total bilirubin must be =< 2 x ULN, or 2) elevated bilirubin believed by investigator to be due to leukemic infiltration, in which case total bilirubin must be =< 2 x ULN.
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
• Creatinine, serum =< 1.5 ULN OR creatinine clearance >= 40 mL/min
• QT interval by Fridericia's correction formula (QTcF) =< 470 msec
• Cohort 1 Patients Only
• Age >= 60 years.
• No prior treatment for ALL except a single dose of intrathecal chemotherapy, corticosteroids, hydroxyurea, and/or leukapheresis to reduce peripheral blast count and prevent ALL complications. Allowed therapy may be administered for no more than 14 days and must be completed >= 24 hours prior to the initiation of protocol therapy.
• No plan for allogeneic or autologous hematopoietic cell transplantation (HCT).
• Cohort 2 Patients Only:
• Age >= 18 years.
• Relapsed or refractory disease in salvage 1 or 2.
• No isolated extramedullary relapse.
• Prior allogeneic HCT permitted.
• Patients with prior allogeneic HCT must have completed transplantation >= 4 months prior to registration.
• Patients with prior allogeneic HCT must have no evidence of graft-versus-host disease and must have completed immunosuppressive therapy >= 30 days prior to registration.
• Prior treatment with inotuzumab ozogamicin, blinatumomab, other CD22-directed therapy, or other CD19-directed therapy is not allowed.
• Prior treatment with rituximab must be completed >= 7 days prior to registration.
• Prior treatment with other monoclonal antibodies must be completed >= 6 weeks prior to registration.
• Prior treatment for ALL must be completed >= 14 days prior to registration with the following exceptions: intrathecal chemotherapy, hydroxyurea, corticosteroids, 6-mercaptopurine, methotrexate, vincristine, and/or leukapheresis to reduce circulating absolute lymphoblast count to =< 10,000/uL or prevent complications related to ALL are allowed but must be completed >= 24 hours prior to the initiation of protocol therapy.
• Patients should have resolution of any acute non-hematologic toxicities of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade =< 1.
• Peripheral blood absolute lymphoblast count =< 10,000/uL (treatment allowed as above to reduce blast count to =< 10,000/uL)

• Patients with a locally advanced or metastatic malignancy, that has progressed following systemic therapy for their disease, if available, or for which the patient is not a candidate or refuses.
• Tumors harboring a MEK or atypical BRAF alteration.
• Provide signed and dated informed consent prior to initiation of any study-related procedures that are not considered standard of care (SoC).
• Male or female patients aged ≥18 years.
• Patients must have measurable disease by RECIST version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0
•2.
• Adequate renal function [creatinine ≤1.5 times ULN (upper limit of normal)] or a glomerular filtration rate (GFR) of ≥50 mL/min (using Cockcroft-Gault).
• Adequate hepatic function [total bilirubin ≤1.5 times ULN; AST (aspartate transaminase) and ALT (alanine transaminase) ≤3 times ULN or ≤5 times ULN if the elevation is due to liver involvement by tumor].
• Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x 109 cells/L; absolute neutrophil count ≥1.5 x 109 cells/L).
• Adequate cardiac function: Left ventricular ejection fraction (LVEF) of >50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and a corrected QT interval (QTc) <480ms by the Fridericia method (QTcF).
• Contraception
•women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal (no menstrual cycle for at least 12 consecutive months), or compliant with a medically approved contraceptive regimen during and for 3 months after the last administration of study drug. Abstinence is not considered an adequate contraceptive regimen.
• Contraception
•men: Must be surgically sterile, or compliant with a medically approved contraceptive regimen during and for 3 months after the last administration of study drug.
• Willing and able to participate in the trial and comply with all trial requirements.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agent may be included after consultation with the medical monitor.
• Gastrointestinal (GI) condition that could impair absorption of study medication (specific cases e.g., remote history of GI surgery, may be enrolled after discussion with the medical monitor) or inability to ingest study medication.
• Uncontrolled or severe intercurrent medical condition.
• Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants, with no dose change in the previous 4 weeks, can be allowed.
• Having received any cancer-directed therapy (chemotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. Patients previously treated with radiotherapy must have recovered from the acute toxicities associated with such treatment.
• Major surgery within 4 weeks prior to first dose.
• Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. A minimum of 10 days between termination of the prior investigational drug and administration of study drug is required. In addition, any drug-related toxicity except alopecia should have recovered to Grade 1 or less.
• Prior therapy with any ERK inhibitor (e.g. LY3214996, LTT462).
• Groups 1-4: Prior therapy with any BRAF and/or MEK inhibitor (e.g. encorafenib, dabrafenib, vemurafenib, binimetinib, trametinib, cobimetinib) is excluded. Prior BRAF and/or MEK inhibitor therapy is permitted for Groups 5 and 6.
• For Part B, agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician's choice
• Pregnant or breast-feeding women.
• Any evidence of serious active infections. Patients are allowed to enroll if they have been fever-free for at least 48 hours and are on an active treatment that is not prohibited in Appendix 1 of the protocol.
• Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study (based on the investigator's judgment).
• A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
• Concurrent therapy with any other investigational agent.
• Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2, CYP2D6, and CYP3A4.

• Pregnant, intending to continue pregnancy, enrolled in the CFF registry
• None

Key
• ≥ 18 years old
• Body mass index (BMI) of ≥ 18 kg/m2
• Documented diagnosis of CF
• Evidence of chronic pulmonary Pseudomonas aeruginosa infection
• Willing to undergo sputum induction procedures at designated study visits, and willing to provide expectorated sputum samples at all other timepoints (for subjects who are able to expectorate)
• FEV1 ≥ 60% of predicted normal [per Global Lung Function Initiative (GLI) standards] at Screening
• Adequate renal function Key
• Recent significant weight loss
• Abnormal vital signs at Screening
• History of prolonged QT syndrome
• Use of supplemental oxygen during the day at rest
• Abnormal liver function tests greater than 3X the upper limit of normal (ULN)
• Recent oral or IV antibiotics received for acute pulmonary exacerbation. Inhaled antibiotic use for chronic suppression of P. aeruginosa is acceptable.
• Recent clinically significant infection requiring systemic antimicrobial therapy
• Currently receiving anti-pseudomonal antibiotic treatment for acute sinusitis.
• Currently receiving systemic corticosteroids
• Currently receiving treatment for active infection with nontuberculous mycobacteria (NTM), Staphylococcus aureus, or Burkholderia cepacia complex lung infection
• Currently receiving treatment for aspergillosis or ABPA (allergic bronchopulmonary aspergillosis)
• Initiation of a CFTR potentiator/corrector therapy, such as Trikafta®, less than 90 days prior to Screening
• Acquired or primary immunodeficiency syndromes
• Active pulmonary malignancy (primary or metastatic)
• History of lung transplantation
• Recent hemoptysis
• Female pregnant or breastfeeding
• Heavy smoker

Key
• Heterozygous for F508del and a minimal function mutation (F/MF genotype)
• Forced expiratory volume in 1 second (FEV1) value >=40% and <=90% of predicted mean for age, sex, and height for participants currently receiving ELX/TEZ/IVA therapy; FEV1 >=40% and <=80% for participants not currently receiving ELX/TEZ/IVA Key
• History of solid organ or hematological transplantation
• Hepatic cirrhosis with portal hypertension, moderate hepatic impairment (Child Pugh Score 7 to 9), or severe hepatic impairment (Child Pugh Score 10 to 15)
• Lung infection with organisms associated with a more rapid decline in pulmonary status
• Pregnant or breast-feeding females Other protocol defined Inclusion/Exclusion criteria may apply

Key
• Participant has one of the following genotypes:
• Homozygous for F508del;
• Heterozygous for F508del and a gating (F/G) mutation;
• Heterozygous for F508del and a residual function (F/RF) mutation;
• At least 1 other TCR CFTR gene mutation identified as responsive to ELX/TEZ/IVA and no F508del mutation
• Forced expiratory volume in 1 second (FEV1) value >=40% and <=90% of predicted mean for age, sex, and height for participants currently receiving CFTR protein modulator therapy; FEV1 >=40% and <=80% for participants not currently receiving CFTR protein modulator therapy Key
• History of solid organ or hematological transplantation
• Hepatic cirrhosis with portal hypertension, moderate hepatic impairment (Child Pugh Score 7 to 9), or severe hepatic impairment (Child Pugh Score 10 to 15)
• Lung infection with organisms associated with a more rapid decline in pulmonary status
• Pregnant or breast-feeding females Other protocol defined Inclusion/Exclusion criteria may apply