• Male patients with moderately severe or severe congenital haemophilia B with a Factor IX activity level below or equal to 2% according to medical records
• Age below or equal to 12 years (until patient turns 13 years, at time of inclusion)
• Body weight above or equal to 10 kg
• History of at least 50 exposure days (EDs) to other FIX products
• The patient and/or parent(s)/caregiver are capable of assessing a bleeding episode, keeping an electronic diary (eDiary), capable of conducting home treatment and otherwise able to follow trial procedures
• Known history of FIX inhibitors
• Current FIX inhibitors above or equal to 0.6 Bethesda Units (BU)
• Congenital or acquired coagulation disorder other than haemophilia B
• Platelet count below 50,000/mcL at screening
• Alanine aminotransferase (ALT) above 3 times the upper limit of normal reference ranges at screening
• Creatinine level above or equal to 1.5 times above the upper normal limit of normal reference ranges at screening
• Human immunodeficiency virus (HIV) positive, defined by medical records, and with a CD4+ lymphocyte count below or equal to 200/mcL
• Immune modulating or chemotherapeutic medication (except single pulse treatment, inhaled and topical steroids)
• Previous arterial thrombotic events (myocardial infarction and intracranial thrombosis, as defined by medical records)

1. Female or male subjects ≥18 years-of-age. 2. Histologically or cytologically documented diagnosis of MDS according to the World Health Organization (WHO) classification (Vardiman 2009, Arber 2016) with >5% and <20% bone marrow blasts by morphology and a peripheral white blood cell (WBC) count of <20,000/μL
• If WBC ≥20,000/μL, cytoreduction with hydroxyurea is permitted prior to enrollment.
• CMML-1 and CMML-2 subtypes 3. Classified as high or very high risk according to the Revised International Prognostic Scoring System (IPSS-R) risk category. CMML-1 and CMML-2 subtypes will be considered high-risk MDS and will not require IPSS-r scoring 4. Bone marrow biopsy (BMBx) and/or aspirate within 28 days prior to first study treatment. 5. Clinical indication for treatment with azacitidine. 6. Previously untreated with HMAs (prior therapy with transfusions, hematopoietic growth factors, or immunosuppressive therapy is allowed). a. subjects who require the start of an HMA (e.g., azacitidine) due to progressing MDS may receive up to 1 cycle of azacitidine within 30 days prior to planned first dose (Cycle 1 Day 1) 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 8. Adequate organ function as evidenced by:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN).
• Total bilirubin ≤1.5 × ULN or total bilirubin of ≤2 mg/dL, whichever is higher. Total bilirubin < 3 x ULN for patients with Gilbert-Meulengracht Syndrome
• Serum creatinine <1.5 mg/dL, or creatinine clearance>40 mL/min.
• QTcF interval ≤450 msec using the mean of triplicate electrocardiograms (ECGs). 9. Female subjects of childbearing potential and male subjects with female partners of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 30 days following last dose. Female subjects of childbearing potential must not be breastfeeding, or planning to breastfeed, and must have a negative pregnancy test ≤7 days before first study drug administration. Male subjects must also refrain from donating sperm during their participation in the study. 10. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care. 11. Have the willingness and ability to understand the nature of this study and to comply with the study and follow-up procedures. 1. Bone marrow blasts ≥20%, indicating a diagnosis of acute myeloid leukemia (AML). 2. Received any of the following within the specified time frame prior to administration of study medication:
• Any investigational agent within 14 days or 5 half-lives prior to enrollment, whichever is longer.
• Hydroxyurea within 48 hours prior to first day of study treatment.
• Hematopoietic growth factors: erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists at least 7 days (14 days for Aranesp), prior to study enrollment.
• Major surgery within 28 days prior to first study treatment. 3. Subjects who have not recovered from side effects of previous therapy. 4. Cardiopulmonary function criteria:
• Current unstable arrhythmia requiring treatment.
• History of symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV).
• History of myocardial infarction, pulmonary embolism or cerebrovascular accident within 6 months of enrollment.
• Current unstable angina. 5. Prior treatment for MDS with HDAC inhibitors Zolinza (vorinostat), Belenodaq (belinostat), Farydak (panobinostat), Istodax (romidepsin/depsipetide), or investigational agent with significant action as an HDAC inhibitor. 6. Clinical evidence of central nervous system involvement. 7. Subjects with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis). 8. Uncontrolled infection with human immunodeficiency virus (HIV) or chronic hepatitis B or C. 9. Life-threatening illness unrelated to cancer or any serious medical or psychiatric illness that could, in the Investigator's opinion, potentially interfere with participation in this study. 10. Presence of a malignant disease within the last 12 months, with the exception of adequately treated in-situ carcinomas, basal or squamous cell carcinoma, non-melanomatous skin cancer, or malignancies treated with curative intent and no evidence of active disease in prior 12 months and felt to be low risk for recurrence. Other malignancies may be considered after consultation withthe Medical Monitor 11. An unwillingness or inability (including breastfeeding women, prohibited concomitant medications, uncontrolled infections, psychological, familial, sociological, or geographical conditions) to comply with study and/or follow-up procedures as outlined in the protocol 12. Known hypersensitivity to any components of pracinostat, azacitidine or mannitol 13. Current smoking or vaporizing of tobacco or cannabis-related products (use of patches, chewing tobacco, or nicotine gum is permitted). Subjects who stopped smoking at least 8 days prior to first pracinostat dosing can be, provided they refrain from smoking during the whole study.

1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell [WBC] <13,000/μL) or low-blast acute myelogenous leukemia (AML). 2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):
• Very high (>6 points).
• High (>4.5-6 points).
• Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts. 3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2. 4. Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score >=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers. Calculation of TRM score:
• 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years).
• + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
• + 0 for (platelets <50), +1 for (platelets >50). 1. Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug. 2. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis. 3. Participants with AML with a WBC count >50,000/ microliter (mcL).. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria. 4. Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:
• Age >75.
• Comorbidities.
• Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM >=4).
• Physician decision (e.g., lack of available stem cell donor).
• The reason a participant is not eligible should be documented in the electronic case report form (eCRF). 5. Has either clinical evidence of or history of central nervous system involvement by AML. 6. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. 7. Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. 8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. 9. Has prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment. 10. Has known human immunodeficiency virus (HIV) seropositive. 11. Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. 12. Has known hepatic cirrhosis or severe preexisting hepatic impairment. 13. Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. 14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.

• Completion of a qualifying Ra Pharmaceuticals sponsored RA101495 PNH study
• Evidence of ongoing clinical benefit in the opinion of the Investigator Exclusion criteria:
• History of meningococcal disease
• Current systemic infection or suspicion of active bacterial infection

• Patients must have histologically confirmed, relapsed/refractory ALK+ ALCL (with ALK positivity defined by immunohistochemistry and/or fluorescence in situ hybridization [FISH]/cytogenetics from any prior biopsy), MCL, or BCL6+ DLBCL (with BCL6 positivity defined by immunohistochemistry from any prior biopsy) and meet the following criteria:
• Patients must have measurable disease that has not been previously irradiated, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional imaging or >= 10 mm with spiral computed tomography (CT) scan; if the patient has been previously irradiated, there must be evidence of progression since the radiation
• Please note, this trial includes mandatory tumor biopsies pre-treatment, during cycle 1 and at the time of disease progression of accessible tumor; having accessible tumor for biopsy is not required for eligibility; we expect that at least 80% of patients will have accessible tumor for these biopsies, however
• ALK+ ALCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included a multiagent chemotherapy regimen including an anthracycline, if not contraindicated, and prior brentuximab; prior crizotinib or other ALK inhibitor therapy, while recommended, is not mandatory; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
• MCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included a multiagent chemotherapy regimen and prior ibrutinib or other BTK inhibitor therapy; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
• BCL6+ DLBCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included an anthracycline, if not contraindicated; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 3 months
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 75,000/mcL, unless due to marrow involvement by lymphoma in which case a platelet count of >= 30,000/mcL will be used
• Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome or hemolysis, in which case =< 3.0 x ULN is allowed
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
• Creatinine =< 1.5 x ULN or a creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Potassium above the institutional lower limit of normal (supplementation to meet this is allowed)
• Magnesium above the institutional lower limit of normal (supplementation to meet this is allowed)
• Human immunodeficiency virus (HIV)+ patients are eligible for the trial provided they meet the other study criteria in addition to the following:
• CD4+ T-cells >= 250/mm^3
• HIV sensitive to antiretroviral therapy
• Zidovudine not allowed
• Long term survival anticipated on the basis of HIV alone were it not for the lymphoma
• No concurrent acquired immunodeficiency syndrome (AIDS)-defining illness other than the lymphoma
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after the completion of AT13387 (onalespib) administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of AT13387 (onalespib) administration
• Patients must be willing to not take St. John wort or grapefruit juice while participating in this trial and should avoid drugs that are strong inducers of P-gp, and to switch to alternative drugs when available
• Ability to understand and the willingness to sign a written informed consent document
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; steroids for symptom palliation are allowed, but must be either discontinued or on stable doses at the time of initiation of protocol therapy
• Patients who are receiving any other investigational agents; all investigational agents other than ibrutinib must have been discontinued at least 4 weeks prior to beginning treatment; prior ibrutinib therapy must have been discontinued at least 2 weeks prior to beginning therapy
• Patients with known leptomeningeal or brain metastases should be excluded from this clinical trial; imaging or spinal fluid analysis to exclude central nervous system (CNS) involvement is not required, unless there is clinical suspicion by the treating investigator
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AT13387 (onalespib)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• There will be no exclusion of patients with known visual impairment or symptoms, including by not limited to peripheral flashes (photopsia), blurred or double vision, floaters, color distortion and dimness, difficulties with light/dark accommodation, tunnel vision or other field defects, halos, apparent movement of stationary objects, and complex disturbances; patients will have a baseline ophthalmologic exam to serve as a point of comparison and further exams as needed should visual symptoms develop; no pretreatment eye exam findings or ocular symptoms have been associated with an increased risk of ocular toxicity seen with AT13387
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AT13387 (onalespib)
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
• Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least three years; patients with prostate cancer are allowed if prostate specific antigen (PSA) is less than 1
• Patients should not receive immunization with attenuated live vaccine within one week of study entry or during study period
• History of noncompliance to medical regimens
• Consistent corrected QT (QTc) > 450 msec for men and > 470 msec for women by Fridericia formula, on 3 separate electrocardiograms (ECGs)
• Left ventricular ejection fraction (LVEF) < 50%, regardless of whether there are symptoms of heart failure

• Children with life-threatening hematological malignancies, deemed eligible for allogeneic stem cell transplantation
• Children with non-malignant disorders amenable to be cured by an allograft
• Lack of HLA identical donor
• Life expectancy > 10 weeks
• Lansky/Karnofsky score > 50
• Grade >II acute GvHD or chronic extensive GvHD at the time of inclusion
• Patient receiving an immunosuppressive treatment for GvHD treatment at the time of inclusion
• Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 ml / min)
• Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction <40%)
• Current active infectious disease (including positive HIV serology or viral RNA)
• Serious concurrent uncontrolled medical disorder
• Pregnant or breast feeding female patient

• ELIGIBILITY CRITERIA FOR SCREENING BIOPSY (STEP 0)
• Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration; patients that are pregnant or breast feeding are excluded; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of study; should a woman become pregnant or suspect while she or her partner is participating in this study, she should inform her treating physician immediately
• Patients must have histologically documented solid tumors or histologically confirmed diagnosis of lymphoma or multiple myeloma requiring therapy and meet one of the following criteria:
• Patients must have progressed following at least one line of standard systemic therapy and there must not be other approval/standard therapy available that has been shown to prolong overall survival (i.e. in a randomized trial against another standard treatment or by comparison to historical controls); patients who cannot receive other standard therapy that has been shown to prolong overall survival due to medical issues will be eligible, if other eligibility criteria are met; if the patient is currently receiving therapy, the clinician must have assessed that the current therapy is no longer benefitting the patient prior to enrolling on MATCH, regardless of whether it is considered standard OR
• Patients for whose disease no standard treatment exists that has been shown to prolong overall survival
• NOTE: No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer; in situ cervical cancer; adequately treated stage I or II cancer from which the patient is currently in complete remission; any other cancer from which the patient has been disease-free for 5 years
• Patients must have measurable disease
• Patients must meet the criteria below and have received results from one of the designated outside laboratories indicating a "rare variant" that is an actionable Mutation of Interest (aMOI) for specific select subprotocols.
• The following requirements apply:
• The outside laboratory specifically notified the site that patient may be a potential candidate for MATCH due to a detected "rare variant"; the outside lab reports are NOT sufficient for this purpose
• NOTE: The content and format of these specific notifications for the Outside Assay process will vary depending on the designated outside lab in question, as they are each responsible for their own outreach efforts; it is strongly recommended that the designated outside laboratory be contacted to confirm the format and receipt of this notification prior to registering any patients to Step 0
• Patients with an applicable "rare variant" must be able to meet the eligibility criteria for the appropriate subprotocols within 4 weeks following notification of treatment assignment
• NOTE: The receipt of this notification (and the start of the associated deadline for Step 1 registration) may occur shortly after Step 0 registration, since these patients will not be submitting tissue for screening purposes; however, for certain "rare variant" arms, submission of archival tissue for central immunohistochemistry (IHC) testing may be required
• Registration to Step 0 must occur after stopping prior systemic anti-cancer therapy; there is no specific duration for which patients must be off treatment prior to registration to Step 0, as long as all eligibility criteria are met
• There is no particular window of time after notification of potential eligibility from an outside lab in which the patient must be registered to Step 0, but treatment slots will be assigned on a first come, first serve basis to those who do register to Step 0, and are not held for those notified of potential eligibility who do not register to Step 0
• Patients may have received other non-targeted, immunotherapy or targeted treatment between the prior genetic testing at the outside lab and registration to Step 0; the decision to stop such treatment in favor of participation in MATCH, if no further clinical benefit is expected, is per the treating physician's discretion; documentation of a lack of response to the prior treatment is not required in these cases
• NOTE: Other potential aMOIs that would be eligibility criteria for "NON RARE" arms, as determined by the designated laboratories, are not applicable for this process in MATCH
• NOTE: Tumor tissue for the confirmation of "rare variant" by the MATCH assay is to be submitted, preferably from the same time of collection as that evaluated by the designated outside laboratory
• Patient must not require the use of full dose coumarin-derivative anticoagulants such as warfarin; low molecular weight heparin is permitted for prophylactic or therapeutic use; factor X inhibitors are permitted
• NOTE: Warfarin may not be started while enrolled in the EAY131 study
• Stopping the anticoagulation for biopsy should be per site standard operating procedure (SOP)
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 and a life expectancy of at least 3 months
• Patients must not currently be receiving any other investigational agents
• Patients must not have any uncontrolled intercurrent illness including, but not limited to:
• Symptomatic congestive heart failure (New York Heart Association [NYHA] classification of III/IV)
• Unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration to Step 0, 2, 4, 6
• Cardiac arrhythmia (ongoing cardiac dysrhythmias of National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4 grade >= 2)
• Psychiatric illness/social situations that would limit compliance with study requirements
• Intra-cardiac defibrillators
• Known cardiac metastases
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (ECHO) (as clinically indicated); (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
• NOTE: To receive an agent, patient must not have any uncontrolled intercurrent illness such as ongoing or active infection; patients with infections unlikely to be resolved within 2 weeks following screening should not be considered for the trial
• Patients must be able to swallow tablets or capsules; a patient with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
• Patients who are human immunodeficiency virus (HIV)-positive are eligible if:
• CD4+ cell count greater or equal to 250 cells/mm^3
• If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; for experimental cancer therapeutics with CYP3A/4 interactions, protease inhibitor therapy is disallowed; suggested regimens to replace protease inhibitor therapy include dolutegravir given with tenofovir/emtricitabine; raltegravir given with tenofovir and emtricitabine; once daily combinations that use pharmacologic boosters may not be used
• No history of non-malignancy acquired immune deficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
• Probable long-term survival with HIV if cancer were not present
• Any prior therapy, radiotherapy (except palliative radiation therapy of 30 gray [Gy] or less), or major surgery must have been completed >= 4 weeks prior to start of treatment; all adverse events due to prior therapy have resolved to a grade 1 or better (except alopecia and lymphopenia) by start of treatment; palliative radiation therapy must have been completed at least 2 weeks prior to start of treatment; the radiotherapy must not be to a lesion that is included as measurable disease
• NOTE: Prostate cancer patients may continue their luteinizing hormone-releasing hormone (LHRH) agonist
• NOTE: For patients entering the study via the original screening process, patients may receive non-protocol treatment after biopsy (if clinically indicated) until they receive notification of results; however, lack of response must be documented prior to registration to Step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; the only intervening treatment permitted is prior therapy that the patient already received prior to Step 0 registration; the decision to stop the intervening non-protocol treatment will be left up to the treating physician if patient has an aMOI; however, patients will need to be off such therapy for at least 4 weeks before receiving any MATCH protocol treatment
• NOTE: For patients entering the study via a designated outside laboratory, no intervening systemic non-protocol treatment is permitted after Step 0 registration; all other eligibility requirements still apply to these patients, including the washouts for prior therapy noted above in this section, the time restrictions outlined, and the eligibility criteria for the intended subprotocol
• Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy >= 4 weeks prior to start of treatment
• Patients must have discontinued steroids >= 1 week prior to registration to Step 0 and remain off steroids thereafter, except as permitted (see below); patients with glioblastoma (GBM) must have been on stable dose of steroids, or be off steroids, for one week prior to registration to treatment (Step 1, 3, 5, 7)
• NOTE: The following steroids are permitted (low dose steroid use is defined as prednisone 10 mg daily or less, or bioequivalent dose of other corticosteroid):
• Temporary steroid use: e.g. for computed tomography (CT) imaging in setting of contrast allergy
• Low dose steroid use for appetite
• Chronic inhaled steroid use
• Steroid injections for joint disease
• Stable dose of replacement steroid for adrenal insufficiency or low doses for non-malignant disease
• Topical steroid
• Steroids required to manage toxicity related to study treatment, as described in the subprotocols
• Steroids required as pre- or post-chemotherapy medication for acceptable intervening chemotherapy
• NOTE: Steroids must be completed alongside last dose of chemotherapy
• Leukocytes >= 3,000/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Absolute neutrophil count >= 1,500/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Platelets >= 100,000/mcL (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• NOTE: Patients with documented bone marrow involvement by lymphoma are not required to meet the above hematologic parameters, but must have a platelet count of at least 75,000/mcL and neutrophil count of at least 1,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin =< 3 x institutional ULN is permitted) (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (up to 5 times ULN in presence of liver metastases) (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• As defined by the Cockcroft-Gault equation (within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration)
• Patients must have an electrocardiogram (ECG) within 8 weeks prior to registration to screening step and must meet the following cardiac criteria:
• Resting corrected QT interval (QTc) =< 480 msec
• NOTE: If the first recorded QTc exceeds 480 msec, two additional, consecutive ECGs are required and must result in a mean resting QTc =< 480 msec; it is recommended that there are 10-minute (+/- 5 minutes) breaks between the ECGs
• The following only need to be assessed if the mean QTc > 480 msec
• Check potassium and magnesium serum levels
• Correct any identified hypokalemia and/or hypomagnesemia and may repeat ECG to confirm exclusion of patient due to QTc
• For patients with heart rate (HR) 60-100 beats per minute (bpm), no manual read of QTc is required
• For patients with baseline HR < 60 or > 100 bpm, manual read of QT by trained personnel is required, with Fridericia correction applied to determine QTc
• Patient must not have hypokalemia (value < institutional lower limit of normal)
• No factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
• NOTE: Patient must be taken off prohibited medication prior to registration to the screening step (Step 0, 2, 4, 6) and remain off these medications thereafter, unless permitted on a subprotocol for the management of treatment related toxicity; patient must be off the drug for at least 5 half-lives prior to registration to the treatment step (Step 1, 3, 5, 7); the medication half-life can be found in the package insert for Food and Drug Administration (FDA) approved drugs
• ELIGIBILITY CRITERIA FOR FIRST TREATMENT (STEP 1)
• If patients have been biopsied or submitted archived tumor tissue obtained within the last 6 months for assessment with the MATCH assays, patients may receive non-protocol treatment after biopsy/tissue submission (if clinically indicated) until they receive notification of results however, lack of response must be documented prior to registration to step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; for pat

• At least 6 years of age.
• Documented diagnosis of sickle cell disease.
• Diagnosis of vaso-occlusive crisis necessitating admission to the hospital with treatment including IV opioids.
• Able to receive the first dose of study drug within 24 hours from the administration of IV opioids.
• Serious systemic infection
• Acute Chest Syndrome
• Serious concomitant medical problems (for example, stroke)
• SCD pain atypical of VOC
• Severe renal or hepatic impairment
• Chronic pain rather than a presentation of acute VOC

Key 1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation. 2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease. -To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:
• Early first relapse (< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL)
• Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR
• Failing to achieve a CR from original diagnosis after at least 1 induction attempt 3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment. 4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2, or for children<2 years of age, ≥ 50mL/min/1.73 m2. 5. Adequate liver function, defined as both of the following:
• Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome
• Alanine aminotransferase (ALT) ≤ 5 × institutional ULN 6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively. Key 1. Known allergy to any of the drugs used in the study. (Subjects who have had a previous allergy to PEG-asparaginase but can receive Erwinia are eligible.) 2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) 3. Left ventricular fractional shortening < 30% 4. History of ≥ Grade 2 pancreatitis 5. Active graft‑versus‑host disease requiring systemic treatment 6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment 7. Down Syndrome 8. Prior therapy restrictions:
• Subjects must have completed therapy with granulocyte‑colony stimulating factor (G‑CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered.
• Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
• At least 3 antibody half‑lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab, 69 days for epratuzumab and 30 days for inotuzumab) before subjects may initiate study treatment.
• Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
• Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation

• Adult patients > 18 years with histologically or cytologically confirmed Peripheral T-cell lymphoma (PTCL)
• Diseases refractory/relapsed after one or more systemic cytotoxic therapies; patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Patients with an ECOG performance status of 0, 1, or 2, and estimated survival of > 12 weeks.
• Patients with at least ONE of the following sites of measurable disease according to International Workshop Criteria87: A) Measurable tumor on MRI or CT scan. Measurable is defined as at least one lesion 20 mm in at least one dimension; for spiral CT, measurable is defined as 10 mm in at least one dimension. For patients with persistent disease, a biopsy of bone marrow, or bone, or a soft tissue site, must have demonstrated viable tumor. If lesion was radiated, biopsy must have been done at least 4 weeks after radiation completed. B) Bone marrow with tumor cells seen on routine morphology (not by NSE staining only) of bilateral aspirate and/or biopsy on one bone marrow sample, except for patient who tested positive subsequent to their last treatment regimen or patients who had a negative marrow within three months of study entry.
• Unable to give written informed consent
• Patients who have received chemotherapy within 3 weeks of first fenretinide treatment, or who have received investigational drugs within 6 weeks of first fenretinide treatment. Patients must have otherwise recovered from toxicities of prior therapy.
• Patient is not eligible if radiation was given to the only site of measurable disease unless there has been subsequent disease progression at that site, or a biopsy of that site showed viable tumor at least 4 weeks after radiation was completed. Patients must not have received small field (focal) radiation for a minimum of 2 weeks prior to study entry. A minimum of 6 weeks is required following prior large field radiation therapy (i.e. TBI, craniospinal therapy, whole abdomen, total lung, > 50% marrow space)
• Patients who have uncontrolled systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular or respiratory systems.
• Patients with any active hepatitis infections.
• Growth factor(s): Must not have received any hematopoetic growth factors within 7 days of study entry.
• Organ Transplant: Patients may NOT be the recipients of an organ transplant.
• Women who are pregnant and/or lactating.
• Patients who have had major non-biopsy surgery in the last 20 days.
• CNS lesions: A) Patients with CNS parenchymal or meningeal-based lesions that are present at study entry are NOT eligible due to concerns regarding toxicity attribution. B) Who have active CNS disease or a history of cranial irradiation are excluded due to concerns regarding toxicity attribution. Patients with previously treated leptomeningeal disease or brain metastases without evidence of remaining tumor by PET, MRI scan, or spinal fluid will be eligible; however such patients currently taking steroids as prophylaxis against seizures are not eligible.
• Patients with documented allergy to egg products.
• Known history of, or positive test result for human immunodeficiency virus (HIV) infection.
• Patients with fasting serum triglycerides > 300 and/or with hypertriglyceridemia requiring medication (but not patients with hypercholesterolemia: patients with hypercholesterolemia with or without medication are eligible).
• Patients concurrently taking the following drugs are excluded: antioxidants, herbal or other alternative therapy medications, vitamin supplements (especially vitamins A, C, and E) other than at standard multivitamin doses, cyclosporine A or analogue; verapamil; tamoxifen or analogue, ketoconazole, chlorpromazine; RU486; indomethacin; or sulfinpyrazone, tetracycline, nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, and amiodarone. If the patients discontinue usage of the above drugs, they can be eligible for enrollment into the study (screening visit) one week or 5-half lives of the drug in question, whichever is the longer, after the discontinuation. For patients requiring any of these medications, entry is permissible only with permission from the medical monitor.
• Patients with poorly controlled diabetes mellitus with fasting serum glucose concentration over 200 mg/dl or a hemoglobin A1C over 7.5%.
• Patients with any known significant cardiac abnormality.
• Patients with uncontrolled hypertension.
• Participation in any other investigational treatment within the 6 weeks prior to enrollment or concurrent with this study.
• Patients with an identified familial hyperlipidemia disorder.
• Patients with documented allergy to soy products.

1. Male or female between 18 and 85 years old. 2. A wide-neck de novo or non-de novo aneurysm. 3. Appropriate informed consent obtainable as determined by local IRB. 4. Life expectancy > 24 months. 1. Aneurysm rupture within 30 days of enrollment. 2. Bifurcating aneurysms not treatable with coiling. 3. Subject has platelet count of <70,000. 4. Subject has known allergies to nickel-titanium metal. 5. Subject has known allergies to aspirin or heparin. 6. Subject has a life-threatening allergy to contrast (unless treatment for allergy can be tolerated). 7. Subject is currently participating in another clinical research study. 8. Subject is pregnant or breastfeeding. 9. Subject has participated in a drug study within the last 30 days. 10. Subject is unable or unwilling to comply with protocol requirements and obtain required clinical evaluations and follow-up.

• Patients must have B-ALL with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease
• Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of CD22 using a phycoerythrin [PE] fluorophore is strongly recommended)
• In the case of an inadequate aspirate sample (dry tap), flow cytometry of peripheral blood specimen may be substituted if the patient has at least 1000/uL circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
• Patient must have one of the following:
• Second or greater relapse;
• Primary refractory disease with at least 2 prior induction attempts;
• First or greater relapse refractory to at least one prior re-induction attempt
• Relapsed patients previously diagnosed with B-lymphoblastic lymphoma are eligible if they have an M2 or M3 marrow at the time of enrollment on this study
• Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy attempts including two different tyrosine kinase inhibitors (TKIs)
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy, defined as resolution of all such toxicities to =< grade 2 or lower per the inclusion/exclusion criteria prior to entering this study
• Myelosuppressive chemotherapy:
• Patients who relapse while receiving standard maintenance therapy will not be required to have a waiting period prior to enrollment onto this study; otherwise, at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exceptions of hydroxyurea or corticosteroids used for cytoreduction
• Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone; intrathecal chemotherapy given at the time of diagnostic lumbar puncture (LP) to evaluate for relapse prior to study enrollment is allowed
• At least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim
• At least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
• At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody with the exception of blinatumomab; patients must have been off blinatumomab infusion for at least 7 days and all drug related toxicity must have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria
• >= 2 weeks must have elapsed since local palliative radiation therapy (XRT) (small port); >= 3 months must have elapsed if prior cranial or craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if total-body irradiation (TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow irradiation was given
• At least 90 days must have elapsed since stem cell transplant; patient must have had no more than one previous HSCT and currently have no evidence of active graft versus (vs.) host disease (GVHD)
• At least 42 days must have elapsed since chimeric antigen receptor (CAR)-T cell therapy
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• 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 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
• 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
• 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
• 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
• 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
• >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
• Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN for age
• Patients with any prior history of SOS/VOD irrespective of severity
• Patients with isolated central nervous system (CNS), testicular, or other extramedullary site of relapse
• Patients who have been previously treated with InO
• Patients with active optic nerve and/or retinal involvement that would require urgent radiation therapy concurrent with protocol therapy; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal involvement
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving or plan to receive other anti-cancer agents (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy and intrathecal chemotherapy)
• Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are receiving cyclosporine, tacrolimus, or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial; at least 3 half-lives must have elapsed after the last dose of GVHD medications (meds)
• Patients who are currently receiving or plan to receive corticosteroids except as described below
• Systemic corticosteroids may be administered for cytoreduction up to 24 hours prior to the start of protocol therapy, as a premedication for InO and as treatment for allergic reactions or for physiologic replacement/stress dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids are not allowed for other indications
• Patients who have an active uncontrolled infection defined as:
• Positive bacterial blood culture within 48 hours of study enrollment;
• Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with clinical signs of infection; fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability
• A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
• Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection as long as cultures have been negative for at least 48 hours and signs or symptoms of active infection have resolved; for patients with clostridium (c.) difficile diarrhea, at least 72 hours of antibacterial therapy must have elapsed and stools must have normalized to baseline
• Active viral or protozoal infection requiring IV treatment
• Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections; testing to prove negative status is not required for enrollment unless it is deemed necessary for usual medical care of the patient
• Patients known to have one of the following concomitant genetic syndromes: Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
• Women of childbearing potential should be advised to avoid becoming pregnant while receiving InO; women should not breast-feed during treatment with InO and for at least 3 months after the final dose
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within 7 days of starting protocol therapy
• Female patients who are sexually active and of reproductive potential are not eligible unless they agree to use an effective contraceptive method for the duration of their study participation and for 8 months after the last dose of InO
• Men with female partners of childbearing potential should use effective contraception during treatment with InO and for at least 5 months after the last dose of InO
• Lactating females are not eligible unless they agree not to breastfeed their infants
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study

• Documented diagnosis of Arginase I deficiency
• Adequate organ function: Hgb ≥ 10 g/dL, ANC ≥ 1.5 x 109/L, plt count ≥ 100,000/µL; liver transaminase levels ≤ 2.5x ULN, total bilirubin ≤ 2.0 mg/dL; serum creatinine <1.5 x ULN
• If female and of child-bearing potential, has a negative serum pregnancy test within 7 days before enrollment
• If a sexually active (male or female), must be surgically sterile, post-menopausal (female), or must agree to use a physician-approved method of birth control during the study and for a minimum of 30 days after the last study drug administration
• Patient or legal guardian is able and willing to provide written informed consent and to comply with all requirements of study participation (including all study procedures and continuation of prescribed diet without modification) prior to any screening procedures
• Transfusion of ≥ 2 u RBC within 60 days
• Active infection requiring systemic treatment
• Known infection with HIV, Hep B or Hep C
• Severe hyperammonemia requiring hospitalization within 14 days. Had more than one episode of hyperammonemia requiring hospitalization within the 30 days prior to enrollment.
• Current uncontrolled hyperammonemia
• Has a history of hypersensitivity to PEG or any other component of the AEB1102 (Co-ArgI-PEG) formulation
• If female, is lactating or breast feeding PART 2 INCLUSION CRITERION: 1. Did not experience any safety or tolerability event in Part 1 which would preclude continued participation and dosing of AEB1102

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

All subjects must meet the following criteria for admission into the study: 1. Signed informed consent has been obtained. 2. Subject is at least 21 years of age. 3. Diagnosis of mycosis fungoides (MF) or Sézary syndrome (SS) will be based on a combination of histological, clinical, and immunophenotypical criteria. The histological criteria will be based on skin biopsy from the most representative skin area. The diagnostic criteria used for each subject will be specified in the case report forms and the specific classification of MF or SS will be identified. The TNMB system will be used to classify the stage of disease (See Section 8.4 for details). 4. Completion of the mSWAT assessment. 5. A history of pruritus that meets following criteria: At Screening Day -7:
• present on a daily basis for greater than one month prior to Screening Day -7,
• NRS for Pruritus score ≥5 as rated by the subject at the Day -7 Visit. Note: If the score is <5 and subject is taking or has taken a medication which may be affecting pruritus (e.g. systemic antihistamine or topical steroid), and if Investigator and subject agree, subject may washout or continue washout of medication and return for Day -7 Visit procedures after washout. At Baseline Period 1 Day 0:
• NRS for Pruritus score of at least 5 recorded in the subject diary on at least 4 of the 7 days preceding Baseline Period 1 Day 0. 6. Pruritic treatment area of 5-95% of the subject's total treatable body surface area. 7. Subject can be expected to reliably follow treatment instructions and visit schedule. 8. Non-pregnant, non-lactating females of childbearing potential who agree to use medically acceptable forms of birth control (abstinence, hormonal contraceptives, diaphragm with spermicide, condom with spermicide, or intrauterine device) throughout the study or females of non-childbearing potential (surgically sterile [hysterectomy or bilateral tubal ligation] or post-menopausal ≥ 1 year). A negative urine pregnancy test must be confirmed at Baseline screening for all female subjects who are not post-menopausal > 1 year or surgically sterile. 9. The subject agrees not to begin any new concomitant medications during their participation in the study, with the exception of medications necessary to treat infection, and to continue any concomitant medication throughout the study. 10. Subject has no visual or motor impairments that will make it difficult to complete the Daily Diary or apply the study medication. 11. Subject is able to speak, read, and write English and agrees to participate and comply with the study procedures. 12. Subject has a body mass index (BMI) between 18.5 and 30.5 kglm2 (see Appendix C, Body Mass Index Table) (subjects in PK subset only). Subjects meeting any of the following criteria will be excluded from study participation: 1. Pregnant or lactating female. 2. History of clinically significant heart failure. 3. Myocardial infarction within the past six months. 4. A history of ventricular arrhythmia requiring treatment. 5. Any medical condition which would, in the Investigator's opinion, preclude the subject from successfully participating in the study. 6. A known allergy to naloxone hydrochloride or any excipient in the formulation. 7. Previous naloxone use for pruritus. 8. Positive urine drug screen at Day 0 for opiates. Positive urine drug screen for anything other than opiates not explained, e.g., by concomitant medication, would also exclude the subject. 9. Treatment with any of the following during the restricted time period prior to Day -7, and at any time during the study, is not allowed: Medication/Treatment Restriction: Systemic narcotic analgesics (e.g. morphine, codeine) 7 days, Topical antihistamines to any skin surface [e.g. Zonalon® (doxepin)] 7 days, Other investigational drugs (excluding any therapies for the treatment of MF or SS) 30 days

• First relapse of B-ALL, allowable sites of disease include isolated bone marrow, combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular; extramedullary sites are limited to the CNS and testicles
• No waiting period for patients who relapse while receiving standard maintenance therapy
• Patients who relapse on frontline therapy in phases other than maintenance must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy (methotrexate strongly preferred) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status
• Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• Stem cell transplant or rescue: patient has not had a prior stem cell transplant or rescue
• Patient has not had prior treatment with blinatumomab
• With the exception of intrathecal chemotherapy (methotrexate strongly preferred; cytarabine is permissible) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status, patient has not received prior relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of first relapse)
• 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
• 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 to < 2 years: =< 0.6 mg/dL
• 2 to < 6 years: =< 0.8 mg/dL
• 6 to < 10 years: =< 1 mg/dL
• 10 to < 13 years: =< 1.2 mg/dL
• 13 to < 16 years: =< 1.5 mg/dL (males) and =< 1.4 mg/dL (females)
• >= 16 years: =< 1.7 mg/dL (males) and =< 1.4 mg/dL (females)
• Direct bilirubin < 3.0 mg/dL
• Shortening fraction of >= 27% by echocardiogram, or
• Ejection fraction of >= 50% by radionuclide angiogram
• All patients and/or their parent or legal guardian 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 Philadelphia chromosome positive/breakpoint cluster region protein (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible
• Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia are not eligible
• Patients with T-lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LL) are not eligible
• Patients with B-lymphoblastic lymphoma (B-LL) are not eligible
• Patients with known optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
• Patients known to have one of the following concomitant genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome
• Patients with known human immunodeficiency virus (HIV) infection
• Patients with known allergy to mitoxantrone, cytarabine, or both etoposide and etoposide phosphate (Etopophos)
• Lactating females who plan to breastfeed
• Patients who are pregnant; pregnancy test is required for female patients of childbearing potential
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
• Patients with pre-existing significant central nervous system pathology that would preclude treatment with blinatumomab, including: history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement are not eligible; patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible; (patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved)
• Patients with uncontrolled seizure disorder are not eligible; (patients with seizure disorders that do not require antiepileptic drugs, or are well controlled with stable doses of antiepileptic drugs remain eligible)

Key
• Ability of the participant's legally authorized representative (e.g. their parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local subject privacy regulations.
• Weight ≥3.5 kg at the time of screening.
• Severe hemophilia A defined as <1 IU/dL (<1%) endogenous FVIII documented in the medical record or as tested during the Screening Period Key
• Any exposure to blood components, factor VIII replacement products, including commercially available rFVIIIFc at any time prior to or during screening.
• Other coagulation disorder(s) in addition to hemophilia A.
• Any concurrent clinically significant major disease that, in the opinion of the Investigator, would make the participant unsuitable for enrollment.
• Current systemic treatment with chemotherapy and/or other immunosuppressant drugs. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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

• Subjects with histologically or cytologically NSCLC, melanoma, transitional cell carcinoma of the genitourinary (GU) tract, renal cell cancer, triple negative breast cancer, adenocarcinoma of the endometrium or squamous cell carcinoma of the head and neck (Phase 1).
• Subjects with histologically confirmed melanoma, NSCLC, transitional cell carcinoma of the GU tract, TNBC, SCCHN, ovarian cancer, MSI high colorectal cancer (CRC), RCC, gastric cancer, HCC and DLBCL (Phase 2).
• Life expectancy > 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status 0
•1.
• Presence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Lugano Classification for subjects with DLBCL.
• Laboratory and medical history parameters within protocol-defined range.
• For Phase 1: Subjects who have advanced or metastatic disease as noted above that have received at least one prior therapy or have advanced or metastatic disease for which no curative treatment is available may be enrolled.
• For Phase 2 expansion cohorts: Subjects with NSCLC, melanoma (checkpoint inhibitor naïve, primary refractory melanoma, relapsed melanoma), transitional cell carcinoma of the GU tract, SCCHN, ovarian cancer, MSI high CRC, RCC, DLBCL, and TNBC.
• Phase 2 expansion: NSCLC
• Subjects who have received at least 1 prior platinum-based therapy. Subjects who have a non-platinum-based regimen may be enrolled with medical monitor approval.
• Tumors with epidermal growth factor receptor mutation positive or anaplastic lymphoma kinase fusion oncogene positive treated with a tyrosine kinase inhibitor are permitted; however, subjects should have progressed on or be intolerant to the targeted therapy.
• Subjects must not have received immunotherapy with programmed death receptor-1 (PD-1) or cytotoxic T-lymphocyte antigen (CTLA-4) targeted therapy.
• Phase 2 expansion: Melanoma
• Documentation of V600E-activating BRAF mutation status.
• Prior systemic therapy requirements.
• Melanoma immune checkpoint-naïve: Subjects must not have received immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. Exception: Prior anti−CTLA-4 in the adjuvant setting would be permitted.
• Primary refractory melanoma: Subjects must have received prior treatment with anti-PD-1 or anti-PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and have progressive disease as their best response to treatment that is confirmed 4 weeks later.
• Relapsed melanoma: Subjects must have received prior anti−PD-1 or anti−PD-L1 therapy (alone or as part of a combination) in the advanced or metastatic setting and achieved partial response ore complete response but later have confirmed progressive disease.
• Subjects enrolling in the primary refractory or relapsed melanoma must be willing to undergo mandatory pretreatment and on-treatment biopsies.
• Ocular melanoma is excluded.
• Phase 2 expansion: Transitional cell carcinoma of the GU tract
• Metastatic or locally advanced and not amenable to curative therapy with disease progression on or after platinum-based chemotherapy or alternative therapy if platinum-based therapy is not appropriate.
• Prior PD-1 or CTLA-4 targeted therapies are excluded
• Phase 2 expansion: SCCHN
• Histologically confirmed metastatic or recurrent squamous cell carcinoma not amenable to local therapy with curative intent (surgery or radiation with or without chemotherapy). Carcinoma of the nasopharynx, salivary gland, or * *Subjects must have received at least 1 prior systemic chemotherapy regimen that must have included a platinum-based therapy.
• Prior PD-1 or CTLA-4 targeted therapies are excluded.
• Phase 2 expansion: Ovarian cancer
• Subjects with FIGO Stage Ic, Stage II, Stage III, Stage IV, recurrent, or persistent (unresectable) histologically confirmed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma.
• Subjects must have received a platinum-taxane-based regimen as first-line therapy.
• Prior PD-1 or CTLA-4 targeted therapies are excluded.
• Borderline, low-malignant-potential epithelial carcinoma per histopathology is excluded.
• Phase 2 expansion: Relapsed or refractory DLBCL
• Prior allogeneic stem-cell transplantation is excluded.
• Must have received > or = 1 prior treatment regimen.
• Not a candidate for curative therapy or hematopoietic stem-cell transplantation (either due to disease burden, fitness, or preference).
• Prior PD-1 or CTLA-4 targeted therapies are excluded.
• Phase 2 expansion: TNBC
• Histologically confirmed breast adenocarcinoma that is unresectable loco regional, or metastatic
• Pathologically confirmed as triple negative, source documented, defined as both of the following:
• Estrogen receptor (ER) and progesterone receptor (PgR) negative.
• Human epidermal growth factor receptor 2 (HER2) negative as per American Society of Clinical Oncology/College of American Pathologists guidelines.
• Subject must have received at least 1 prior systemic regimen for advanced or metastatic disease
• Prior PD-1 or CTLA-4 targeted therapies are excluded.
• Phase 2 expansion: RCC
• Subjects with histological or cytological confirmation of clear cell RCC.
• Not curable by surgery.
• Subjects must have received prior antiangiogenic therapy.
• Subjects must not have received prior immunotherapy with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy.
• Phase 2 expansion: MSI high CRC
• Subjects with histological confirmation of locally advanced unresectable or metastatic MSI high CRC.
• MSI status is, respectively, determined by examining CRC tumor.
• Subjects may have received no more than 2 lines of prior therapy for advanced disease.
• Phase 2 expansion: Gastric Cancer
• Must have histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma.
• Must have progression on or after therapy containing platinum/fluoropyrimidine or refused standard therapy.
• Subjects may have received no more than 2 lines of prior therapy for advanced disease.
• Prior PD-1 or CTLA-4 targeted therapies are excluded.
• Phase 2 expansion: HCC
• Must have histologically or cytologically confirmed diagnosis of HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).
• Barcelona Clinic Liver Cancer (BCLC) Stage C disease (Llovet et al 1999), or BCLC Stage B disease.
• Subjects may have received no more than 2 lines of prior therapy for the advanced disease
• Must have progressed on, refused, or were intolerant of sorafenib.
• The following are excluded: Subjects with liver transplants, clear invasion of the bile duct or main portal branch(es), or hepatorenal syndrome, or subjects who have required esophageal variceal ablation within 28 days of starting study treatment.
• Prior PD-1 or CTLA-4 targeted therapies are excluded.
• Tumor biopsies are required. If a subject has inaccessible lesions, such as in ovarian cancer, HCC, or gastric cancer, or highly vascular lesions, such as RCC, enrollment may be considered with medical monitor approval, and archived tissue may be acceptable.
• Females of child-bearing potential and males who use adequate birth control through 120 days post dose.
• Subjects who participated in any other study in which receipt of an investigational study drug or device occurred within 2 weeks or 5 half-lives (whichever is longer) prior to first dose.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Exception: Prior anti−CTLA-4 in the adjuvant setting for subjects with melanoma would be permitted.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable.
• Has an active autoimmune disease.
• Has evidence of noninfectious pneumonitis that required steroids or current pneumonitis.
• Live vaccine use within 30 days of first dose of study medication.
• Monoamine oxidase inhibitors.

• Subjects must be newly diagnosed or previously diagnosed with CNL or aCML; all patients must have a bone marrow biopsy completed during the screening or baseline period if one has not been done within 90 days of day 1, cycle one
• Subjects must have platelet count greater than 25,000 per microliter at baseline and at the start of study (day 1, cycle 1) visit
• Subjects must be able to discontinue any drug treatment aimed at lowering disease burden in CNL or aCML; subjects should discontinue hydroxyurea to treat underlying CNL or aCML disease no later than day -7 (one week before starting ruxolitinib); for drugs that have more long-lasting effects on the marrow, such as thalidomide and its analogs, and interferon, subjects should discontinue these no later than day -28
• Subjects must be willing to accept/continue transfusions to treat low hemoglobin levels
• Subjects must have a life expectancy of > 6 months
• Subjects unable to review and sign informed consent form
• Females who are pregnant or breastfeeding, and males and females who cannot comply with requirements to avoid fathering a child or becoming pregnant
• Subjects with known diagnosis of human immunodeficiency virus (HIV) or chronic active Hepatitis B or C; viral testing is not required; subjects with a history of Hepatitis B and/or C are allowed on trial if the virus is undetected at the time of enrollment
• Subjects with inadequate liver (alanine aminotransferase [ALT]/serum glutamate pyruvate transaminase [SGPT] above 4 X upper limit of normal [ULN] or direct bilirubin 4 X ULN AND the lab abnormalities are felt to be due to underlying liver dysfunction)
• Subjects with end stage renal function (creatinine clearance [CrCl] < 15 mL/min or glomerular filtration rate [GFR] <15 mL/min) regardless of whether hemodialysis is required
• Subjects with clinically serious infections requiring ongoing antibiotic therapy
• Subjects with severe (immediately life threatening) and recent (occurring within the last 3 months) cardiac dysfunction, pulmonary dysfunction, esophageal variceal bleeding, hemorrhagic strokes, or intracranial hemorrhage are not eligible for study participation
• Subjects requiring therapeutic doses of anticoagulation or anti-platelet therapies (aspirin above 81 mg daily, Plavix or similar agents) AND platelet counts are below 50,000 on two different laboratory evaluations, separated by minimum of two weeks
• Taking investigational or commercial agents or therapies with the intent to treat the subject's malignancy other than those therapies permitted
• Subjects with invasive malignancy over the previous 2 years except treated early stage carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix, and completely resected papillary thyroid and follicular thyroid cancers
• Previous allergic reactions to janus kinase (JAK) inhibitors or excipients
• Prior therapy with ruxolitinib or other JAK inhibitors
• Subjects who have had major surgery within 4 weeks prior to entering the study
• Subjects who are anticipated to receive a transplant within the first 6 months of treatment on trial

• Diagnosis of advanced solid tumor cancer, lymphoma, or myeloma (no time restrictions or limitations) -OR- diagnosis of early stage solid tumor cancer, lymphoma, or myeloma <= 12 months prior to study enrollment
• Diagnosis of VTE <= 30 days prior to study enrollment for which potential benefits of anticoagulation therapy to prevent recurrence of VTE are felt by the treating physician to exceed the potential harms
• Any anticoagulation drug/strategy may be used to treat the index VTE; protocol treatment will begin <= 30days after the index VTE diagnosis date
• Treating physician intends to put participant on anticoagulation therapy for at least three months.
• Age >= 21 years
• Platelet count is >= 50,000/mm^3 (<= 7 days prior to enrollment)
• CrCl (Creatinine Clearance) is >= 15 ml/min (<= 7 days prior to enrollment)
• Diagnosis of acute leukemia
• Has ever received or is scheduled to receive an Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)
• Patients who have ever received an Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) ARE eligible.
• Patients who are scheduled to receive an Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) are NOT eligible
• Ongoing, clinically significant bleeding (CTCAE grade 3 or 4)
• Ongoing therapy with a P-gp inhibitor (e.g., nelfinavir, indinavir, or saquinavir-protease inhibitors for HIV) as these drugs interact with the factor Xa inhibitors
• Therapy with any azole antifungals (e.g., itraconazole, ketaconazole, voriconazole) at the time of enrollment

• Patients must have had histologic verification of juvenile myelomonocytic leukemia (JMML) at original diagnosis and currently have relapsed or refractory disease; the diagnosis is made based on the following criteria
• JMML category 1 (all of the following): the diagnostic criteria must include all features in category 1 and EITHER (i) one of the features in category 2 OR (ii) two features from category 3 to make the diagnosis
• Splenomegaly
• > 1000 (1 x 10^9/uL) circulating monocytes
• < 20% blasts in the bone marrow or peripheral blood
• Absence of the t(9;22) or BCR/ABL fusion gene
• JMML category 2 (at least one of the following if at least two category 3 criteria are not present):
• Somatic mutation in RAS or PTPN11
• Clinical diagnosis of NF1 or NF1 gene mutation
• Homozygous mutation in CBL
• Monosomy 7
• JMML category 3 (at least two of the following if no category 2 criteria are met):
• Circulating myeloid precursors
• White blood cell count, > 10 000 (10 x 10^9/ uL)
• Increased hemoglobin F for age
• Clonal cytogenetic abnormality
• GM-CSF hypersensitivity
• Patients with refractory or relapsed JMML must have had at least one cycle of intensive frontline therapy or at least 2 cycles of a deoxyribonucleic acid (DNA) demethylating agent with persistence of disease, defined by clinical symptoms or the presence of a clonal abnormality; frontline therapy is defined as one cycle of intravenous chemotherapy that includes of any of the following agents: fludarabine, cytarabine, or any anthracycline but specifically excludes oral 6-mercaptopurine; frontline therapy will also include any conditioning regimen as part of a stem cell transplant; patients who transform to AML at any point with more than 20% blasts are not eligible for this trial
• Patients must have a Lansky or Karnofsky performance status score of >= 50, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment
• Myelosuppressive chemotherapy: patients must have completely recovered from all acute toxic effects of chemotherapy, immunotherapy or radiotherapy prior to study enrollment; at least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of hydroxyurea
• Note: cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy
• Hematopoietic growth factors: at least 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
• Biologic (anti-neoplastic agent): at least 7 days must have elapsed since completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur
• Monoclonal antibodies:
• At least 30 days after the completion of any type of immunotherapy, e.g. tumor vaccines
• At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody
• Radiotherapy:
• >= 2 weeks must have elapsed since local palliative external radiation therapy (XRT) (small port)
• >= 6 months must have elapsed if prior craniospinal XRT was received, if >= 50% of the pelvis was irradiated, or if traumatic brain injury (TBI) was received
• >= 4 weeks must have elapsed if other substantial bone marrow irradiation was given
• Stem cell transplant or rescue without TBI: no evidence of active graft versus (vs.) host disease and >= 3 months must have elapsed since transplant
• Patients must not be known to be refractory to red blood cell or platelet transfusions
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: Maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male) 0.4 (female)
• 6 months to < 1 year: 0.5 (male) 0.5 (female)
• 1 to < 2 years: 0.6 (male) 0.6 (female)
• 2 to < 6 years: 0.8 (male) 0.8 (female)
• 6 to < 10 years: 1 (male) 1 (female)
• 10 to < 13 years: 1.2 (male) 1.2 (female)
• 13 to < 16 years: 1.5 (male) 1.4 (female)
• >= 16 years: 1.7 (male) 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN (=< 135 U/L) (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin >= 2 g/dL
• Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by multi-gated acquisition (MUGA)
• Corrected QT (by Bazett's formula [QTcB]) interval < 450 msecs
• Patients must be able to swallow tablets or liquid; use of a nasogastric or gastrostomy (G) tube is also allowed
• Patients who are pregnant or breast-feeding are not eligible for this study as there is yet no available information regarding human fetal or teratogenic toxicities; negative pregnancy tests must be obtained in girls who are post-menarchal; patients of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy; women of childbearing potential should be advised to use effective contraception for 4 months after the last dose of trametinib; breastfeeding women are excluded; female patients should not breastfeed during treatment with trametinib, and for 4 months following the last dose; male patients must use a condom during intercourse and agree not to father a child during therapy and for 4 months following discontinuation of trametinib to avoid unnecessary exposure of trametinib to the fetus
• Concomitant Medications
• Corticosteroids: patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Note: hydrocortisone used as a pre-medication to prevent transfusion related reactions is not considered a concomitant corticosteroid
• Investigational drugs: patients who are currently receiving another investigational drug are not eligible
• Anti-cancer agents: patients who are currently receiving other anti-cancer agents are not eligible (except patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
• Anti-graft versus host disease (GVHD) or agents to prevent organ rejection post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial
• Cardiac medications: any medications for treatment of left ventricular systolic dysfunction
• Patients who have an uncontrolled infection are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
• Patients with a history of hepatic sinusoid obstructive syndrome (veno-occlusive disease) within the prior 3 months
• Patients with a history of current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
• Patients with a history of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension)
• Uncontrolled systemic disease(s) such as hypertension or diabetes mellitus; blood pressure must be =< the 95th percentile for age, height, and gender
• History of allergic reaction attributed to compounds of similar chemical or biologic composition to the MEK inhibitor, trametinib
• Patients who are able to swallow capsules or liquid or able to use a nasogastric or G tube are eligible

• Patient must be a newly diagnosed ALL, in first remission
• Patient must have completed curative chemotherapy within past 90 days at a Childrens Oncology Group (COG) institution
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Lansky for patients =< 16 years of age
• At the time of consent, patient or parent/guardian reports less than 420 minutes of moderate to vigorous physical activity over the last week
• Patient must have access to a smart phone with Android 4.3 or later or iOS 7.1 or later or computer (laptop/desktop) with a connection to the internet to create an account and be able to sync the Sqord device (accelerometer)
• Patient and at least one parent/guardian are able to read and write English; at least 1 parent/guardian must be able to read and write English in order to assist the patient with using their Sqord account
• Patients with previous hematopoietic stem cell transplant (HSCT)
• Patients with significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with protocol therapy, or interfere with consent, study participation, follow up, or interpretation of study results
• Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test
• Female patient who is postmenarcheal has agreed to use an effective contraceptive method (including abstinence) for the duration of study participation

• MDS classified as follows:
• RAEB-1 per World Health Organization (WHO) MDS criteria (5% to <10% BM blasts)
• RAEB-2 per WHO MDS criteria (10% to <20% BM blasts)
• RAEB-t per French-American-British (FAB) classification (20% to 30% BM blasts)
• At least one cytopenia (ANC < 1800/µL or platelet count < 100,000/µL or hemoglobin [Hgb] < 10 g/dL)
• Progression (according to 2006 IWG criteria) at any time after initiation of AZA or DAC treatment or Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC administered or Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
• Duration of prior HMA therapy ≤ 9 months and/or total ≤ 9 cycles of prior HMA therapy in ≤ 12 months
• Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
• Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogeneic stem cell transplantation
• Off all treatments for MDS (including AZA and DAC) for ≥ 4 weeks before randomization; growth factors (G-CSF, erythropoietin and thrombopoietin) and transfusions are allowed before and during the study as clinically indicated
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Willing to adhere to protocol prohibitions and restrictions
• Patient must sign informed consent form to indicate patient's understanding study's purpose and procedures and willingness to participate. Should patient be incapable of giving consent, the patient's legally authorized representative (as defined by local regulation) must give consent. However, should patient, in any manner, choose not to participate this takes precedence and will be respected.
• Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide, where available and indicated
• Previous participation in a clinical study of IV or oral rigosertib; patients who failed screening for other rigosertib studies may be screened for participation
• Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside plus 2-3 days of an anthracycline, or high-dose cytarabine
• Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell transplant or a suitable donor cannot be found
• Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ that is unlikely to progress in two years
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
• Active infection not adequately responding to appropriate therapy
• Total bilirubin ≥1.5 mg/dL not related to hemolysis or Gilbert's disease
• Alanine transaminase (ALT)/aspartate transaminase (AST) ≥2.5 x upper limit of normal (ULN)
• Serum creatinine ≥2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) < 40 mL/min.
• Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:
• HIV or hepatitis C
•presence of viral load
• Hepatitis B
•antigen positive
• Uncorrected hyponatremia (defined as serum sodium value of <130 mEq/L)
• Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day non-treatment follow-up period. Examples of acceptable contraception methods include:
• estrogen-gestagen based contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal),
• gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable),
• intra-uterine devices (IUDs),
• intra-uterine hormone-releasing systems (IUSs),
• bilateral tubal occlusion
• vasectomized partner
• sexual abstinence in accordance with an individual's lifestyle
• Female patients of child-bearing potential (pre-menopausal and not surgically sterilized) who are breast-feeding or have a positive blood beta-human chorionic gonadotropin pregnancy test at Screening
• Major surgery without full recovery or within 3 weeks before planned randomization;
• Uncontrolled hypertension
• New onset seizures (within 3 months before planned randomization) or poorly controlled seizures
• Any other concurrent investigational agent or chemotherapy, radiotherapy, immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions)
• Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted to the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization
• Investigational therapy within 4 weeks of planned randomization
• Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
• Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage of >30%).

• PRE-REGISTRATION
• Diagnostic bone marrow and peripheral blood specimens must be submitted for immunophenotyping and selected molecular testing, and the establishment of BCR/ABL status; testing will be performed by the Eastern Cooperative Oncology Group (ECOG)-American College of Radiation Imaging Network (ACRIN) Leukemia Translational Research Laboratory (LTRL) and reported to the institution
• NOTE: IT IS ESSENTIAL THAT A SAMPLE CONTAINING SUFFICIENT BLAST CELLS BE SUBMITTED TO THE ECOG-ACRIN LTRL AT BASELINE SO THAT SUBSEQUENT BONE MARROW ASSESSMENTS OF MRD CAN BE DONE; IN ADDITION TO ALLOWING THE LTRL TO CONFIRM ELIGIBILITY BASED ON BLAST CELL IMMUNOPHENOTYPE AND BCR/ABL STATUS, IT IS ALSO IMPERATIVE THAT AN ADEQUATE NUMBER OF BLASTS BE BANKED FOR ANALYSIS BY DRS MULLIGHAN/WILLMAN. WITHOUT ADEQUATE BASELINE SAMPLES, PATIENTS WILL NOT BE ABLE TO BE TREATED AND RANDOMIZED ON THIS PROTOCOL; IF A BONE MARROW ASPIRATE IS NOT AVAILABLE FOR LTRL SUBMISSION AT BASELINE, IT IS IMPERATIVE THAT DR PAIETTA FROM THE LTRL IS CALLED TO DISCUSS THE PERIPHERAL BLOOD WBC AND BLAST COUNT BEFORE BLOOD ONLY IS SUBMITTED
• NOTE: Hydroxyurea can be given for up to 5 days prior to initiation of protocol therapy for control of leukocyte count and/or other symptoms or signs; corticosteroids can be given after pre-registration to the protocol and submission of baseline marrow and blood samples for control of leukocyte count and/or other symptoms or signs prior to initiation of protocol therapy if needed; if corticosteroids are given prior to pre-registration, contact the study chair as the patient may still be eligible to participate
• INDUCTION ELIGIBILITY CRITERIA-STEP 1
• New diagnosis of B lineage ALL must be made upon bone marrow or peripheral blood immunophenotyping; cases with myeloid antigen expression, but unequivocal lymphoid immunophenotype, are eligible
• Mature B ALL (Burkitt's-like leukemia) is excluded from enrollment in this trial; pre-study bone marrow biopsy and aspirate must be completed =< 1 week prior to registration
• Negativity for the Philadelphia chromosome must be established by conventional cytogenetics, fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR); patients who are negative for the Philadelphia chromosome by conventional cytogenetics must have FISH or PCR performed for BCR/ABL to exclude occult translocations
• Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts from peripheral blood; FISH testing for common B-lineage ALL abnormalities including t(9;22) (BCR/ABL1), t(12;21) (ETS-variant gene 6 [ETV6]/runt-related transcription factor 1 [RUNX1]), t(1;19) (pre-B-cell leukemia homeobox 1 [PBX1]/transcription factor 3 [TCF3]), +4,+10,+17, (centromeric [Cen]4/Cen10/Cen17), t(11q23;var), (myeloid/lymphoid or mixed lineage leukemia [MLL]), deletion (del)(9p) (cyclin-dependent kinase inhibitor 2A [CDKN2A]/Cen9), and t(14;var) (immunoglobulin heavy chain [IGH] is encouraged); if there are few or no circulating blasts and an adequate marrow sample cannot be obtained for cytogenetic analysis, the patient may still enroll on the trial
• Patient must not have a concurrent active malignancy for which they are receiving treatment
• Serum direct bilirubin < 2 mg/dl or serum total bilirubin =< 3; NOTE: the above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration
• Serum creatinine < 2 mg/dl; NOTE: the above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration
• Patient should be human leukocyte antigen (HLA) typed (A, B, C, DR and DQ) during induction therapy phase or a written explanation for not undergoing HLA typing on the flow sheet
• Patient must not have intercurrent organ damage or medical problems that will jeopardize the outcome of therapy (i.e., psychiatric disorder, drug abuse, pregnancy)
• Patients with known human immunodeficiency virus (HIV) infection are eligible if they meet all of the following criteria:
• No history of acquired immune deficiency syndrome (AIDS)-related complications other than a history of low CD4+ T-cell count (< 200/mm^3) prior to initiation of combination antiretroviral therapy; on study CD4+ T-cell count may not be informative due to leukemia and should not be used as an exclusion criterion if low
• Patient must be healthy on the basis of HIV disease with high likelihood of near normal life span were it not for the leukemia
• Patient must have serum HIV viral load of < 200 copies/mm^3
• Patient must be on combination antiretroviral therapy with minimal pharmacokinetic interactions with study therapy and minimal overlapping clinical toxicity with protocol therapy
• Patient must not be receiving protease inhibitors or once daily formulations containing cobicistat, stavudine, or on regimens containing stavudine or zidovudine
• It is recommended to utilize a regimen of the integrase inhibitor, dolutegravir, combined with either disoproxil fumarate/emtricitabine or dolutegravir combined with tenofovir alafenamide/emtricitabine
• Patient must not have an antecedent hematologic disorder
• Patient must have no history of recent myocardial infarction (within three months), uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia
• Patient must not have a history or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia; Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, or other significant CNS abnormalities
• Patient must have a normal cardiac ejection fraction by pretreatment multigated acquisition scan (MUGA) or echocardiogram within 4 weeks prior to registration (resting ejection fraction >= 40% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within the normal range of values for the institution
• Patient must not have an active uncontrolled infection
• Women must not be pregnant or breast-feeding and must not become pregnant or breastfeed during protocol therapy and for at least 3 months after protocol therapy; woman of childbearing potential must abstain from sexual activity or be willing to use 2 highly effective forms of contraception throughout protocol therapy and for at least an additional 3 months after the last dose of protocol-specified therapy; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Men who have a female partner of childbearing potential must be willing to use 2 highly effective forms of contraception throughout protocol therapy and for at least an additional 3 months after the last dose of protocol-specified therapy; men who have a pregnant partner must be willing to use a condom during sexual activity throughout protocol therapy and for 3 months after the last dose of protocol-specified therapy
• ECOG performance score 0-3
• Patient must have given written informed consent
• POST-INDUCTION THERAPY ELIGIBILITY CRITERIA (PRIOR TO INTENSIFICATION-STEP 2)
• ECOG performance status 0-2
• Patients must have achieved a CR or CRi
• Patients who have achieved a CR or CRi must have maintained peripheral blood evidence of a CR or CRi
• Patient must be CNS (cerebrospinal fluid [CSF]) negative for leukemia
• Patients must have resolved any serious infectious complications related to induction
• Any significant medical complications related to induction must have resolved
• Obtained =< 48 hours prior to registration: Serum creatinine =< 2.0 mg/dl
• Obtained =< 48 hours prior to registration: Serum direct bilirubin < 2 mg/dL or serum total bilirubin =< 3
• Obtained =< 48 hours prior to registration: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
• RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3
• Patients must have an ECOG performance status of 0-2
• Patients must have maintained peripheral blood evidence of a remission and must have a CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy
• Patients must have resolved any serious infectious complications related to therapy
• Any significant medical complications related to therapy must have resolved
• Direct or total bilirubin < 1.5 x ULN (unless related to Gilbert's or Meulengracht's syndrome); the values must be obtained within 48 hours prior to randomization
• Serum creatinine < 1.5 x ULN; the values must be obtained within 48 hours prior to randomization
• Bone marrow aspirates must be submitted for centralized minimal residual disease (MRD) assessment performed by the ECOG-ACRIN Leukemia Translational Research Laboratory
• MRD results will be reported to the submitting institution
• NOTE: FOR MRD ASSESSMENTS, AN ASPIRATE FROM A SEPARATE BONE MARROW ASPIRATION SITE MUST BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED THROUGH THE SAME SKIN PUNCTURE SITE); ONLY SUBMIT ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION SITE FOR MRD TESTING; DO NOT SUBMIT SAMPLES FROM THE SECOND OR THIRD PULL OF THE SAME ASPIRATION SITE
• In B-lineage ALL, MRD levels in peripheral blood or from a dilute marrow aspiration can be 300% lower, on average, than those in bone marrow at a given time point; submitting a first pull from a separate aspiration site will ensure that MRD determinations used in randomization and trial interpretation are accurate
• NOTE: failure to submit bone marrow aspirates will result in a major violation at the time of an audit
• CRITERIA FOR ALLOGENEIC TRANSPLANTATION
• A suitable donor must be identified; there are no restrictions on donor type and can include a matched sibling, a matched or mismatched unrelated donor, a family haplotype matched donor or a cord blood donor (single or double)
• Patients should meet the eligibility criteria for RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3
• Patients must be considered reliable enough to comply with the medication regimen and follow-up, and have social support necessary to allow this compliance
• CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have an ECOG performance status of 0-3
• CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have maintained peripheral blood evidence of a remission and must have a CR or CRi, confirmed on restaging BM aspirate and biopsy
• CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have resolved any serious infectious complications related to therapy
• CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Any significant medical complications related to therapy must have resolved

• Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the Part A consent form prior to enrollment on AALL1131
• White Blood Cell Count (WBC) Criteria
• Age 1-9.99 years: WBC >= 50 000/uL
• Age 10-30.99 years: Any WBC
• Age 1-30.99 years: Any WBC with:
• Testicular leukemia
• CNS leukemia (CNS3)
• Steroid pretreatment
• Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization [WHO] classification) (also termed B-precursor acute lymphoblastic leukemia); patients with Down syndrome are also eligible
• Organ function requirements for patients with Ph-like ALL and a predicted TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within 3 days of study entry onto the dasatinib arm of AALL1131
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: Maximum Serum Creatinine (mg/dL)
• 1 to < 6 months: 0.4 (male) 0.4 (female)
• 6 months to < 1 year: 0.5 (male) 0.5 (female)
• 1 to < 2 years: 0.6 (male) 0.6 (female)
• 2 < 6 years: 0.8 (male) 0.8 (female)
• 6 to < 10 years: 1.0 (male) 1.0 (female)
• 10 to < 13 years: 1.2 (male) 1.2 (female)
• 13 to < 16 years: 1.5 (male) 1.4 (female)
• > 16 years: 1.7 (male) 1.4 (female)
• Direct bilirubin =< 3 x upper limit of normal (ULN) for age, and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 x upper limit of normal (ULN) for age
• Shortening fraction >= 27% by echocardiogram, or ejection fraction >= 50% by gated radionuclide study
• Patients must have an electrocardiogram (EKG) fewer than 6 days prior to enrollment on the dasatinib arm; patients who have had cardiac assessments by echocardiogram or radionuclide scan at the beginning of induction do not need to have these repeated prior to study entry; correct QT interval (QTc) < 450 msec on baseline electrocardiogram as measured by the Friderica or Bazett formula
• No major conduction abnormality (unless a cardiac pacemaker is present)
• No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination
• Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided
• Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study
• Patients must be aged 6 to 13 years at time of B-ALL diagnosis, enrolled on AALL1131
• Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available)
• Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation)
• Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli
• Eligibility criteria for the National Cancer Institute (NCI) standard risk patients from AALL0932 enrolling on this study at the end of Induction
• Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the HR B-ALL stratum of this study at the end of Induction:
• Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 8 peripheral blood (PB) minimal residual disease (MRD) >= 1% and day 29 bone marrow (BM) MRD < 0.01%
• With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any day 8 PB MRD and day 29 BM MRD >= 0.01%
• Both NCI standard risk (SR) and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria
• Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum of AALL1131:
• Intrachromosomal amplification of chromosome 21 (iAMP21)
• Mixed-lineage leukemia (MLL) rearrangement
• Hypodiploidy (n < 44 chromosomes and/or a deoxyribonucleic acid [DNA] index < 0.81)
• Induction failure (M3 BM at day 29)
• Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 29 BM MRD >= 0.01%
• Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction:
• Day 29 MRD >= 0.01%
• MLL rearrangement
• Hypodiploidy (n < 45 chromosomes and/or DNA index < 0.81)
• DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction failure (M3 BM day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131)
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met
• 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 any cancer diagnosed prior to the initiation of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving prior steroid therapy may be eligible for AALL1131
• Patients with BCR-ABL1 fusion are not eligible for post-induction therapy on this study but may be eligible to enroll in a successor Children's Oncology Group (COG) Philadelphia positive (Ph+) ALL trial by day 15 Induction
• DS HR B-ALL patients with Induction failure or BCR-ABL1
• Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs
• Lactating females are not eligible unless they have agreed not to breastfeed their infant
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

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

• Children with HbSS or sickle hemoglobin (HbS)/β^0thalassemia
• ≥9 to ≤ 36 months of age at study initiation
• Enrollment will occur irrespective of clinical severity Permanent:
• Receiving chronic red blood cell transfusion therapy.
• Condition or chronic illness, which in the opinion of the PI makes participation unsafe. Transient (participants may be re-evaluated after ≥14 days):
• Recent (<30 days) participation in another clinical intervention trial utilizing an investigational new drug/investigational device exemption (IND/IDE) agent.
• Erythrocyte transfusion in the past 2 months.
• Laboratory Assessments:
• Hemoglobin <6.0 g/dL
• Absolute reticulocyte count <80 * 10^3/µL if hemoglobin <9.0 g/dL
• Absolute neutrophil count <1.5 * 10^3/µL
• Platelet count <100 * 10^3/µL
• Serum creatinine > twice the upper limit of normal for age
• Alanine aminotransferase (ALT) > twice the upper limit of normal

• Participants with 1 to less than (<) 18 years of age (Part 1 only), or 1 to 30 years of age, inclusive, if initial diagnosis of mature B-cell non-Hodgkin lymphoma (NHL) occurred at <18 years of age (Part 2 only)
• Participants must be in first recurrence or have disease that is primarily refractory to conventional therapy
• Participants must have at least 1 of the following: 1 site of measurable disease greater than (>) 1 centimeter (cm) in the longest diameter and >1 cm in the shortest diameter by radiological imaging; bone marrow involvement; cerebrospinal fluid with blasts present
• Participants with lansky-Karnofsky score of greater than or equal to (>=) 50
• Adolescent women/young women of childbearing potential must have a negative highly sensitive serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at Screening before enrollment/randomization. Adolescent/young women who are pregnant or breastfeeding are ineligible for this study
• Participants with ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonists (example phenprocoumon), or ongoing treatment with agents known to be strong CYP3A4/5 inhibitors, or has taken any disallowed therapies as noted in Section 8.2, Prohibited Medications, before the planned first dose of study drug
• Participants with inherited or acquired bleeding disorders
• Participants with clinically significant arrhythmias, complex congenital heart disease, or left ventricular ejection fraction (LVEF) <50 percent (%) or shortening fraction (SF) <=28%
• Participants with known history of human immunodeficiency virus (HIV) or active Hepatitis B or C virus
• Participants with any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel
• Participants with known allergies, hypersensitivity, or intolerance to ibrutinib or its excipients (refer to Investigator's Brochure)
• A diagnosis of post-transplant lymphoproliferative disease (PTLD)
• Participants who are within 6 months of an allogeneic bone marrow transplant
• Participants who have had prior exposure to ibrutinib

• Must have relapsed or refractory acute lymphoblastic leukemia (ALL) or relapsed or refractory lymphoblastic lymphoma (LL). Refractory is defined as persistent disease after at least 2 courses of chemotherapy.
• Participants with ALL with Philadelphia chromosome or with an ABL class targetable fusion are eligible.
• Participants with LL must have radiographic evidence of disease
• Must weigh greater than or equal to 20 kg.
• Must be able to swallow pills.
• Must have adequate hepatic and kidney function.
• Must have adequate performance status:
• Participants less than or equal to 16 years of age: Lansky greater than or equal to 50
• Participants greater than 16 years of age: Karnofsky greater than or equal to 50 or Eastern Cooperative Oncology Group (ECOG) less than 3.
• Participant has central nervous system (CNS) disease with cranial involvement that requires radiation.
• Participants who are less than 100 days post-transplant, or greater than 100 days post-transplant with active graft versus host disease (GVHD), or are still continuing post-transplant immunosuppressant therapy within 7 days prior to the first dose of study drug.
• Participants who have received any of the following prior to the first dose of study drug:
• Inotuzumab within 30 days and must have ALT, AST and bilirubin < ULN.
• A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent within 30 days
• CAR-T infusion or other cellular therapy within 30 days
• Any anti-cancer therapy including blinatumomab, chemotherapy, radiation therapy targeted small molecule agents or investigational agents within 14 days, or 5 half-lives, whichever is shorter
• Exception: Philadelphia Chromosome (Ph)+ ALL subjects on TKIs at Screening may enroll and remain on Tyrosine Kinase Inhibitor (TKI) therapy to control disease
• Steroid therapy for anti-neoplastic intent within 5 days
• Hydroxyurea that is ongoing (hydroxyurea is permitted up to the first dose)
• A strong or moderate CYP3A inhibitor or inducer within 7 days
• Aspirin within 7 days, or 5 half-lives, whichever is longer
• An excluded antiplatelet/anticoagulant drug or a herbal supplement that affects platelet function within 7 days, or 5 half-lives, whichever is longer
• Participants with malabsorption syndrome or any other condition that precludes enteral administration.