A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Phase 2

Suspended

Conditions: Down Syndrome
Recurrent B Acute Lymphoblastic Leukemia

Interventions: Procedure: Biospecimen Collection
Radiation: 3-Dimensional Conformal Radiation Therapy
Biological: Blinatumomab
Procedure: Bone Marrow Aspiration
Procedure: Bone Marrow Biopsy
Drug: Calaspargase Pegol
Drug: Dexamethasone
Drug: Cytarabine
Drug: Hydrocortisone Sodium Succinate
Procedure: Lumbar Puncture
Drug: Methotrexate
Biological: Nivolumab
Drug: Mercaptopurine
Drug: Pegaspargase
Drug: Pegcrisantaspase
Drug: Vincristine Sulfate

Registration Number: NCT04546399

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies the effect of nivolumab in combination with blinatumomab compared to blinatumomab alone in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) that has come back (relapsed). Down syndrome patients with relapsed B-ALL are included in this study. Blinatumomab is an antibody, which is a protein that identifies and targets specific molecules in the body. Blinatumomab searches for and attaches itself to the cancer cell. Once attached, an immune response occurs which may kill the cancer cell. Nivolumab is a medicine that may boost a patient's immune system. Giving nivolumab in combination with blinatumomab may cause the cancer to stop growing for a period of time, and for some patients, it may lessen the symptoms, such as pain, that are caused by the cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To compare event free survival post reinduction (EFS PR) between blinatumomab vs. blinatumomab/nivolumab in Group 4 patients aged ≥ 1 to \<31 years old with first relapse of CD19+ B ALL.

II. To compare EFS PR (EFS post-reinduction) between consolidation with blinatumomab vs. blinatumomab/nivolumab in Group 3 patients aged \>= 1 to \< 31 years old with first relapse of CD19+ B ALL.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of blinatumomab/nivolumab in patients aged \>= 1 to \< 31 years old with first relapse of CD19+ B ALL.

EXPLORATORY OBJECTIVES:

I. In Group 4 patients, compare EFS PR between blinatumomab monotherapy and blinatumomab/nivolumab arms as compared to similar patients treated on the predecessor trial AALL1331.

II. In Group 4 patients, compare toxicity as defined by grade 3 or greater adverse events during the first cycle of blinatumomab or blinatumomab/nivolumab.

III. In Group 4 patients, compare MRD negative second remission (Rem-2) rate after the first cycle of immunotherapy between blinatumomab monotherapy and blinatumomab/nivolumab arms.

IV. In patients with Down syndrome (DS) with first relapse of B-ALL, describe the safety, tolerability and efficacy (as defined by MRD negative second remission, Rem-2) after up to two cycles of blinatumomab/nivolumab.

V. With each Group, perform subset analyses of EFS and overall survival (OS) based on features including degree of marrow disease at relapse, age, sex, body mass index, cytogenetics, site(s) of relapse, percent peripheral blasts at relapse and absolute lymphocyte count at first relapse.

OUTLINE:

Patients \>= 18 years old with marrow +/- extramedullary (EM) relapse of any duration after initial diagnosis, or patients \< 18 years old with marrow +/- EM relapse \< 24 months after initial diagnosis are assigned to Group 1. Patients \< 18 years old with marrow +/- EM relapse \>= 24 months from initial diagnosis, or all isolated extramedullary (IEM) relapses \>= 1 to \< 31 years old are assigned to Groups 2-3 re-induction. Patients with DS are assigned to Arm G. NOTE: Patients in Group 1 and DS patients with white blood cells (WBC) \>= 30,000/uL, CNS 2/3 disease, or testicular disease must first receive 1 of 3 pre-immunotherapy treatments.

Starting with amendment 4C (9/19/2024), patients with DS are assigned to group 3 or 4. Patients \< 18 years with bone marrow first relapse ≥ 36 months from initial diagnosis with MRD \<0.1% after VXLD reinduction or with isolated CNS/testicular extramedullary relapse occurring ≥ 18 months from initial diagnosis with MRD \<0.1% after VXLD reinduction are assigned to group 3. Patients who do not meet criteria for group 3 will be assigned to group 4. Patients with Down syndrome ≥ 1 to \< 31 years of age with first bone marrow relapse of B ALL are assigned to arm G.

PRE-IMMUNOTHERAPY TREATMENT FOR PATIENTS WITH WBC \>= 30,000/uL (CLOSED TO ACCRUAL 9/19/2024 EXCEPT FOR ARM G) : Patients receive methotrexate (MTX) intrathecally (IT) or cytarabine IT or intrathecal triple therapy (ITT) consisting of MTX, hydrocortisone sodium succinate, and cytarabine IT at the time of diagnostic lumbar puncture (LP) or on day 1 (if intrathecal therapy is given with relapse diagnostic LP \< 7 days prior to the start of protocol therapy). Patients also receive dexamethasone intravenously (IV) or orally (PO) twice daily (BID) on days 1-5, vincristine sulfate via infusion or IV IV push over 1 minute on day 1. Patients with DS also receive leucovorin calcium PO or IV every 6 hours (q6h) for 2 doses on day 2 or at 24 and 30 hours after each IT administration. Patients should proceed to the next cycle when CNS 1 and no testicular disease is present, no sooner than Day 8 and no later than Day 15.

PRE-IMMUNOTHERAPY TREATMENT FOR CNS 2/3 DISEASE (CLOSED TO ACCRUAL 9/19/2024 EXCEPT FOR ARM G): Patients receive MTX IT or cytarabine IT twice weekly (Q2W) for 5-7 doses or Intrathecal Triple Therapy (ITT) IT Q2W for 3-4 doses until patient is CNS 1. Patients with DS also receive leucovorin calcium PO or IV q6h for 2 doses at 24 and 30 hours after each IT administration. Patients should proceed to the next cycle when CNS 1 and no testicular disease is present, no sooner than Day 15 and no later than Day 24.

PRE-IMMUNOTHERAPY TREATMENT FOR TESTICULAR DISEASE(CLOSED TO ACCRUAL 9/19/2024 EXCEPT FOR ARM G): Patients receive MTX IT, cytarabine IT, or ITT IT on days 1 and 15 (day 1 may be omitted if intrathecal therapy is given with relapse diagnostic LP \< 7 days prior to the start of protocol therapy). Patients with DS also receive leucovorin calcium PO or IV q6h for 2 doses on days 2 and 16 or at 24 and 30 hours after each IT administration. Males with testicular disease at relapse undergo radiation once daily (QD) for a total of 12 fractions over 12 days. Patients should proceed to the next cycle when CNS 1 and no testicular disease is present, no sooner than Day 15 and no later than Day 22.

GROUP 1 (CLOSED TO ACCRUAL 9/19/2024): Patients are randomized to Arm A or Arm B.

ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2.

ARM B: Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2.

GROUPS 2-4 VXLD REINDUCTION: Patients receive vincristine sulfate via infusion or IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV on days 1-14, doxorubicin hydrochloride IV over 1-15 minutes on day 1, MTX IT on days 1, 8, and 29 (day 1 IT may be omitted if intrathecal therapy is given with relapse diagnostic LP \< 7 days prior to the start of this cycle) (days 8 and 29 for CNS 1 patients at relapse only), pegaspargase intramuscularly (IM) or IV over 1-2 hours on days 2 and 16 or calasparagase IV over 1-2 hours on day 2 (for patients ≤ 22 years), cytarabine IT on days 4 and 11 (CNS 2 patients at relapse only), then Q2W until 3 consecutive samples are clear of blasts, and ITT IT on days 8, 15, 22, and 29 (CNS 3 patients at relapse only). Treatment continues in the absence of disease progression or unacceptable toxicity.

GROUP 2 (CLOSED TO ACCRUAL 9/19/2024): The following patients are randomized to Arm C or Arm D: 1) \>= 1 to \< 31 years old, IEM relapse \< 18 months from diagnosis, regardless of MRD after Re-Induction. 2) \< 18 years old with marrow relapse \>= 24 to \< 36 months from diagnosis regardless of MRD after Re-Induction, 3) \>= 1 to \< 31 years old, IEM relapse \>= 18 months, and MRD \>= 0.1% after Re-Induction, 4) \< 18 years old with marrow relapse \>= 36 months, and MRD \>= 0.1% after Re-Induction.

ARM C: Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and MTX IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal MTX is given \< 7 days prior to the start of cycle 1 ). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2.

ARM D: Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2.

GROUP 3: Patients are randomized to Arm E or Arm F.

ARM E:

IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, and MTX IT on days 1 and 15 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Immunotherapy cycles 1-2 alternate with Consolidation cycles 1-2.

CONSOLIDATION: Patients receive dexamethasone PO or IV on days 1-5, methotrexate IV, over 24 hours, on days 8 and 22, methotrexate IT on days 8 and 22 (CNS 1/2 at relapse only) or ITT IT on days 8 and 22 (CNS 3 at relapse only).

INTENSIFICATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42, methotrexate IV over 24 hours on days 8 and 22, cytarabine IV, over 3 hours on days 43 and 44, asaparaginase erwinia recombiant IM or crisantaspase/asparaginase erwinia IM or IV over 1-2 hours on day 44, methotrexate IT on days 1 and 43 (CNS 1/2 at relapse only) or ITT IT on days 1 and 43 (CNS 3 at relapse only).

IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days 1-28, and MTX IT on days 1 and 15 (CNS 1/2 at relapse only) or ITT IT on days 1 and 15 (CNS 3 at relapse only).

MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61, vincristine sulfate IV push over 1 minute or via infusion on days 1, 29, and 57, mercaptopurine PO on days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT IT on day 1 (CNS 3 patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years from the start of Re-Induction therapy in the absence of disease progression or unacceptable toxicity.

MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS ONLY): Beginning between the first and second cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and 15-21, vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15, and pegaspargase IM or IV over 1-2 hours or calaspargase IV over 1-2 hours on day 1. Patients with CNS 3 and isolated CNS relapse undergo cranial radiation in the form of 3-dimensional (D)-conformal radiation therapy (CRT) over 5 days per week for a total of 10 treatments.

ARM F:

IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and on days 1 of cycles 2 and 3, and MTX IT on days 1 and 15 (CNS 1/2 patients at relapse only)(day 1 may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle) or , ITT IT on day 1 (CNS 3 patients at relapse only) (day 1 may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Immunotherapy cycles 1-2 alternate with Consolidation cycles 1-2.

CONSOLIDATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate IV push over 1 minute or via infusion on day 1, methotrexate IV, over 24 hours, on days 8 and 22, methotrexate IT on days 8 and 22 (CNS 1/2 at relapse only) or ITT IT on days 8 and 22 (CNS 3 at relapse only).

INTENSIFICATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42, methotrexate IV over 24 hours on days 8 and 22, cytarabine IV, over 3 hours on days 43 and 44, asaparaginase erwinia recombiant IM or crisantaspase/asparaginase erwinia IM or IV over 1-2 hours on day 44, methotrexate IT on days 1 and 43 (CNS 1/2 at relapse only) or ITT IT on days 1 and 43 (CNS 3 at relapse only).

IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 1 and 15 and MTX IT on days 1 and 15.

MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61, vincristine sulfate IV push over 1 minute or via infusion on days 1, 29, and 57, mercaptopurine PO on days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT IT on day 1 (CNS 3 patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78. Treatment repeats every 12 weeks for 2 years from the start of Re-Induction therapy in the absence of disease progression or unacceptable toxicity.

MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS): Beginning between the first and second cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and 15-21, vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15, and pegaspargase IM or IV over 1-2 hours or calaspargase IV over 1-2 hours on day 1. Patients with CNS 3 and isolated CNS relapse undergo cranial radiation in the form of 3-dimensional (D)-conformal radiation therapy (CRT) over 5 days per week for a total of 10 treatments.

GROUP 4: Patients are randomized to arm H or arm I.

ARM H: Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 36 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

ARM I: Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS 1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 36 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

ARM G (DS PATIENTS): Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS 1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Recruitment & Eligibility

Status: SUSPENDED

Sex: All

Target Recruitment: 300

Inclusion Criteria

Patients must be >= 1 and < 31 years at time of enrollment
Patients must have first relapse of CD19+ B-ALL (relapse blasts must express CD19) in one of the following categories:
- Isolated bone marrow relapse
- Isolated central nervous system (CNS) (excluding known optic nerve/retinal and CNS chloromas) and/or testicular relapse
- Combined bone marrow with extramedullary relapse in the CNS (excluding known optic nerve/retinal and CNS chloromas) and/or testes
Patients with Down syndrome (DS) are eligible in the following categories:
- Isolated bone marrow relapse
- Combined bone marrow with CNS (excluding known optic nerve/retinal and CNS chloromas) and/or testicular 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
- Of note, for patients with developmental delay (e.g., Down syndrome) regardless of age, Lansky scale may be substituted for Karnofsky scale. However, the requirement for ECOG 0-2 remains, regardless of known history of developmental delay
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
- Patients with prior blinatumomab or CD19+ chimeric antigen receptor therapy in the upfront setting will be eligible, provided relapsed lymphoblasts retain CD19 expression
- Patients must not have had a prior hematopoietic stem cell transplant
- A single intrathecal chemotherapy at the time of relapse will be allowed. If < 7 days have elapsed between this intrathecal therapy (IT) and the start of protocol therapy, then the day 1 intrathecal chemotherapy (i.e. methotrexate, cytarabine, or triple intrathecal) may be omitted
- In the 28 days prior to enrollment, up to five days of post-relapse, pre-enrollment therapy (steroids and/or hydroxyurea only) is permissible
  - Patients with Down syndrome who received pre-enrollment therapy and have a white blood count (WBC) >= 30,000/ul at the time of enrollment still must receive protocol specified cytoreductive therapy with vincristine and dexamethasone, and no "washout" is required
  - Patients with Down syndrome who received pre-enrollment therapy and have a WBC < 30,000/ul at the time of enrollment must be given a 24 hour "washout" before starting immunotherapy
- Note: There is no waiting period or "washout" for patients who relapse while receiving upfront therapy
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/sex as follows (within 7 calendar days prior to enrollment):
- Age: Maximum serum creatinine (mg/dL)
  - 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)
    - The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Center for Disease Control (CDC)
Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by echocardiogram, cardiac magnetic resonance imaging (MRI) or radionuclide angiogram
No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria

Patients with B-lymphoblastic lymphoma (B-LLy)
Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia
Patients with Philadelphia chromosome positive (Ph+) B-ALL
Patients with mixed phenotype acute leukemia (MPAL)
Patients with known Charcot-Marie-Tooth disease
Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype
Patients with active, uncontrolled infection defined as:
- Positive bacterial blood culture within 48 hours of study enrollment
- Receiving IV or PO antibiotics for an infection with continued signs or symptoms. Note: Patients may be receiving IV or oral antibiotics to complete a course of therapy for a prior documented infection if 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.
- Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with clinical signs of infection. Fever without clinical signs of infection that is attributed to tumor burden is allowed if blood cultures are negative for > 48 hours
- A positive fungal culture within 30 days of study enrollment or active therapy for presumed invasive fungal infection
- Active viral or protozoal infection requiring IV treatment
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 are not eligible.
Patients with uncontrolled HIV, hepatitis B, or hepatitis C infection. Of note, patients with known human immunodeficiency virus (HIV) infection on effective anti-retroviral therapy with undetectable viral load for at least the last 6 months prior to enrollment are eligible. Similarly, hepatitis B and hepatitis C positive patients who have been treated and have no viral detectable burden are also eligible
Patients with significant central nervous system pathology that would preclude treatment with blinatumomab, including history of severe neurologic disorder or autoimmune disease with CNS involvement
- Note: Patients with a history of seizures that are well controlled on stable doses of anti-epileptic drugs are 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 an active known/suspected autoimmune disease are not eligible. However, patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
Group 4 and patients with DS patients with known non-hematopoietic, non-CNS/testicular extramedullary disease (i.e., chloromatous disease) are not eligible
- Note: Group 3 patients with known non-hematopoietic, non-CNS/testicular extramedullary disease (i.e., chloromatous disease) are eligible if this is NOT the only site of relapsed disease
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained within 7 days prior to enrollment. 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 this study. Men with female partners of childbearing potential should use effective contraception during the duration of their treatment. The effect of blinatumomab on fertility has not been evaluated. Blinatumomab is not recommended for pregnant women or women of childbearing potential (WOCBP) not using contraception. Females of reproductive potential must use effective contraception during treatment and for at least 48 hours after the last dose of blinatumomab. Studies in animal models have shown that nivolumab can adversely impair pregnancy. Thus, nivolumab is expected to cause fetal harm during pregnancy. WOCBP receiving nivolumab must continue contraception for a period of at least 5 months after the last dose of nivolumab. It is unknown whether nivolumab is present in breast milk, thus breastfeeding should be discontinued while a patient is receiving nivolumab
Lactating females are not eligible unless they agree to not breastfeed their infants. It is unknown whether blinatumomab or its metabolites are excreted in human breast milk. Women are not permitted to breastfeed while receiving blinatumomab and for the last 48 hours after the last blinatumomab dose. Due to the potential for serious adverse reactions in the breastfed infant, women are not permitted to breastfeed during treatment and for 5 months after the last nivolumab dose

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Blinatumomab	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Bone Marrow Aspiration	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Bone Marrow Biopsy	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Bone Marrow Aspiration	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Biospecimen Collection	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Bone Marrow Biopsy	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Bone Marrow Biopsy	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Calaspargase Pegol	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Cytarabine	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Calaspargase Pegol	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Cytarabine	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Bone Marrow Biopsy	See Outline section
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Cytarabine	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Dexamethasone	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Hydrocortisone Sodium Succinate	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Lumbar Puncture	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Methotrexate	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Arm G (dexamethasone, blinatumomab, nivolumab,MTX) DS patients	Nivolumab	Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Biospecimen Collection	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Blinatumomab	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Bone Marrow Aspiration	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Bone Marrow Biopsy	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Biospecimen Collection	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Cytarabine	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Dexamethasone	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Hydrocortisone Sodium Succinate	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Lumbar Puncture	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Blinatumomab	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm A (dexamethasone, blinatumomab, MTX)	Methotrexate	ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1, 15, and 36 of cycle 1 (MTX, cytarabine, and ITT on day 1 may be omitted if intrathecal therapy was given \< 7 days prior to the start of this cycle), and MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Biospecimen Collection	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Blinatumomab	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Bone Marrow Aspiration	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Bone Marrow Biopsy	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Cytarabine	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Dexamethasone	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Hydrocortisone Sodium Succinate	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Lumbar Puncture	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Methotrexate	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 1, Arm B (dexamethasone, blinatumomab, MTX)	Nivolumab	Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Bone Marrow Biopsy	See Outline section
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Dexamethasone	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Lumbar Puncture	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm C (dexamethasone, blinatumomab, MTX)	Methotrexate	Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via continuous IV infusion on days 1-28 of cycles 1 and 2, and methotrexate IT on days 1 and 15 of cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal therapy is given \< 7 days prior to the start of this cycle). Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Biospecimen Collection	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Blinatumomab	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Bone Marrow Aspiration	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Bone Marrow Aspiration	See Outline section
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Dexamethasone	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Lumbar Puncture	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Methotrexate	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX)	Nivolumab	Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients with MRD \< 0.01% after cycle 1 may stop study treatment or may choose to continue to cycle 2. Patients with MRD \>= 0.01% after cycle 1 proceed to cycle 2. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study. (CLOSED TO ACCRUAL 9/19/2024)
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	3-Dimensional Conformal Radiation Therapy	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Biospecimen Collection	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Blinatumomab	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Bone Marrow Aspiration	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Dexamethasone	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Hydrocortisone Sodium Succinate	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Lumbar Puncture	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Mercaptopurine	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Methotrexate	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Pegaspargase	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Pegcrisantaspase	See Outline section
Group 3, Arm E (dexamethasone, blinatumomab, MTX)	Vincristine Sulfate	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	3-Dimensional Conformal Radiation Therapy	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Biospecimen Collection	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Blinatumomab	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Dexamethasone	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Hydrocortisone Sodium Succinate	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Lumbar Puncture	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Mercaptopurine	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Methotrexate	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Nivolumab	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Pegaspargase	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Pegcrisantaspase	See Outline section
Group 3, Arm F (dexamethasone, blinatumomab, nivolumab)	Vincristine Sulfate	See Outline section
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Biospecimen Collection	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Blinatumomab	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Bone Marrow Aspiration	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Bone Marrow Biopsy	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Calaspargase Pegol	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Cytarabine	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Biospecimen Collection	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Dexamethasone	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Hydrocortisone Sodium Succinate	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Lumbar Puncture	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Methotrexate	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4 Arm I (Dexamethasone, blinatumomab, nivolumab)	Nivolumab	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Blinatumomab	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Bone Marrow Aspiration	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Bone Marrow Biopsy	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Cytarabine	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Dexamethasone	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Hydrocortisone Sodium Succinate	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Lumbar Puncture	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.
Group 4, Arm H (dexamethasone bilinatumomab)	Methotrexate	Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only, blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is given with \< 7 days prior to the start of this cycle). Cycles repeat every 37 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of blood, urine and cerebrospinal fluid throughout the study.

Primary Outcome Measures

Name	Time	Method
Minimal residual disease (MRD) negative second remission (Rem-2) rate with blinatumomab vs with blinatumomab + nivolumab (Group 1)	Up to 2 cycles of therapy (each cycle = 36 days)	MRD negative Rem-2 be defined as Rem-2 (i.e., achievement of MRD \< 1% blasts by flow cytometry and resolution of extramedullary disease (for CNS disease, requires CNS 1) ) and bone marrow with MRD \< 0.01% by flow cytometry. MRD negative Rem-2 rate between Arm A vs Arm B will be compared using a one-sided Z test of proportions with Type I error of 0.10. Interim analysis will be conducted to monitor for futility. The futility boundaries are based on testing the alternative hypothesis at the 0.067 level.
Event-free survival post-reinduction (EFS PR) (Group 3)	From date of randomization to date of treatment failure, relapse, disease progression, second malignancy (SMN) or death due to any cause, assessed up to 10 years after completion of enrollment.	Comparison of EFS post reinduction between Arm E versus Arm F will be based on a one-sided two-sample logrank test with Type I error of 0.10, to be conducted 3 years after completion of enrollment of Group 3. Interim analysis will be conducted to monitor for futility. The futility monitoring will be based on testing the alternative hypothesis at the 0.067 level. This alpha level corresponds to that which would cause futility stopping if the one-sided two-sample logrank test shows evidence of a hazard ratio \> 1.0 when half of the expected events are observed.
EFS PR (Group 4)	From date of randomization to date of treatment failure, relapse, disease progression, second malignancy (SMN) or death due to any cause, assessed up to 10 years after completion of enrollment.	Comparison of EFS post reinduction between Arm H versus Arm I will be based on a one-sided two-sample logrank test with Type I error of 0.10, to be conducted 3 years after completion of enrollment of Group 3. Interim analysis will be conducted to monitor for futility. The futility monitoring will be based on testing the alternative hypothesis at the 0.067 level. This alpha level corresponds to that which would cause futility stopping if the one-sided two-sample logrank test shows evidence of a hazard ratio \> 1.0 when half of the expected events are observed.

Secondary Outcome Measures

Name	Time	Method
Dose-limiting toxicity	Up to 1 cycle of therapy (each cycle = 36 days)	Will be assessed using the Common Terminology Criteria for Adverse Events version 5.0.
EFS PR (Group 4)	From date of randomization to date of treatment failure, relapse, disease progression, SMN or death due to any cause, assessed up to 5 years after completion of enrollment	Comparison of EFS post-reinduction between Arm C versus Arm D will be based on a one-sided two-sample logrank test with type I error of 0.15, to be conducted 2 years after completion of enrollment of Group 2. The futility monitoring will be based on testing the alternative hypothesis at the 0.092 level.

Trial Locations

Locations (203): Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
USA Health Strada Patient Care Center
🇺🇸
Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
Kingman Regional Medical Center
🇺🇸
Kingman, Arizona, United States
Banner Children's at Desert
🇺🇸
Mesa, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸
Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
Kaiser Permanente-Anaheim
🇺🇸
Anaheim, California, United States
PCR Oncology
🇺🇸
Arroyo Grande, California, United States
Kaiser Permanente-Bellflower
🇺🇸
Bellflower, California, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
Kaiser Permanente-Fontana
🇺🇸
Fontana, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Kaiser Permanente Los Angeles Medical Center
🇺🇸
Los Angeles, California, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Mattel Children's Hospital UCLA
🇺🇸
Los Angeles, California, United States
Albany Medical Center
🇺🇸
Albany, New York, United States
Valley Children's Hospital
🇺🇸
Madera, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Sutter Medical Center Sacramento
🇺🇸
Sacramento, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Kaiser Permanente-San Diego Zion
🇺🇸
San Diego, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
🇺🇸
Torrance, California, United States
Children's Hospital Colorado
🇺🇸
Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸
Gainesville, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸
Hollywood, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸
Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Sacred Heart Hospital
🇺🇸
Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
Tampa General Hospital
🇺🇸
Tampa, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Saint Mary's Medical Center
🇺🇸
West Palm Beach, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸
Atlanta, Georgia, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
Kapiolani Medical Center for Women and Children
🇺🇸
Honolulu, Hawaii, United States
Saint Luke's Cancer Institute - Boise
🇺🇸
Boise, Idaho, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸
Peoria, Illinois, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
Children's Hospital New Orleans
🇺🇸
New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
🇺🇸
New Orleans, Louisiana, United States
Maine Children's Cancer Program
🇺🇸
Scarborough, Maine, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Tufts Children's Hospital
🇺🇸
Boston, Massachusetts, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Bronson Battle Creek
🇺🇸
Battle Creek, Michigan, United States
Corewell Health Dearborn Hospital
🇺🇸
Dearborn, Michigan, United States
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Corewell Health Grand Rapids Hospitals - Butterworth Hospital
🇺🇸
Grand Rapids, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸
Grand Rapids, Michigan, United States
Trinity Health Grand Rapids Hospital
🇺🇸
Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
West Michigan Cancer Center
🇺🇸
Kalamazoo, Michigan, United States
Ascension Borgess Hospital
🇺🇸
Kalamazoo, Michigan, United States
Trinity Health Muskegon Hospital
🇺🇸
Muskegon, Michigan, United States
Corewell Health Lakeland Hospitals - Niles Hospital
🇺🇸
Niles, Michigan, United States
Cancer and Hematology Centers of Western Michigan - Norton Shores
🇺🇸
Norton Shores, Michigan, United States
Corewell Health Reed City Hospital
🇺🇸
Reed City, Michigan, United States
Corewell Health Children's
🇺🇸
Royal Oak, Michigan, United States
Corewell Health William Beaumont University Hospital
🇺🇸
Royal Oak, Michigan, United States
Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center
🇺🇸
Saint Joseph, Michigan, United States
Corewell Health Lakeland Hospitals - Saint Joseph Hospital
🇺🇸
Saint Joseph, Michigan, United States
Munson Medical Center
🇺🇸
Traverse City, Michigan, United States
Corewell Health Beaumont Troy Hospital
🇺🇸
Troy, Michigan, United States
University of Michigan Health - West
🇺🇸
Wyoming, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Carson Tahoe Regional Medical Center
🇺🇸
Carson City, Nevada, United States
Comprehensive Cancer Centers of Nevada - Henderson
🇺🇸
Henderson, Nevada, United States
Comprehensive Cancer Centers of Nevada-Horizon Ridge
🇺🇸
Henderson, Nevada, United States
Las Vegas Cancer Center-Henderson
🇺🇸
Henderson, Nevada, United States
OptumCare Cancer Care at Seven Hills
🇺🇸
Henderson, Nevada, United States
Comprehensive Cancer Centers of Nevada-Southeast Henderson
🇺🇸
Henderson, Nevada, United States
OptumCare Cancer Care at Charleston
🇺🇸
Las Vegas, Nevada, United States
Hope Cancer Care of Nevada
🇺🇸
Las Vegas, Nevada, United States
Sunrise Hospital and Medical Center
🇺🇸
Las Vegas, Nevada, United States
Ann M Wierman MD LTD
🇺🇸
Las Vegas, Nevada, United States
Comprehensive Cancer Centers of Nevada - Northwest
🇺🇸
Las Vegas, Nevada, United States
OptumCare Cancer Care at MountainView
🇺🇸
Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Comprehensive Cancer Centers of Nevada - Town Center
🇺🇸
Las Vegas, Nevada, United States
Comprehensive Cancer Centers of Nevada-Summerlin
🇺🇸
Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸
Las Vegas, Nevada, United States
Las Vegas Cancer Center-Medical Center
🇺🇸
Las Vegas, Nevada, United States
Comprehensive Cancer Centers of Nevada
🇺🇸
Las Vegas, Nevada, United States
OptumCare Cancer Care at Fort Apache
🇺🇸
Las Vegas, Nevada, United States
Comprehensive Cancer Centers of Nevada - Central Valley
🇺🇸
Las Vegas, Nevada, United States
Hope Cancer Care of Nevada-Pahrump
🇺🇸
Pahrump, Nevada, United States
Renown Regional Medical Center
🇺🇸
Reno, Nevada, United States
Saint Mary's Regional Medical Center
🇺🇸
Reno, Nevada, United States
Cancer Care Specialists - Reno
🇺🇸
Reno, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸
Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Rutgers Cancer Institute of New Jersey
🇺🇸
New Brunswick, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Maimonides Medical Center
🇺🇸
Brooklyn, New York, United States
NYU Langone Hospital - Long Island
🇺🇸
Mineola, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Rochester
🇺🇸
Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸
Stony Brook, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Sanford Broadway Medical Center
🇺🇸
Fargo, North Dakota, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
ProMedica Flower Hospital
🇺🇸
Sylvania, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸
Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Lehigh Valley Hospital-Cedar Crest
🇺🇸
Allentown, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States
Prisma Health Richland Hospital
🇺🇸
Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
Prisma Health Cancer Institute - Eastside
🇺🇸
Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
East Tennessee Childrens Hospital
🇺🇸
Knoxville, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸
Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Dell Children's Medical Center of Central Texas
🇺🇸
Austin, Texas, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸
El Paso, Texas, United States
Cook Children's Medical Center
🇺🇸
Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
Children's Hospital of San Antonio
🇺🇸
San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸
San Antonio, Texas, United States
Primary Children's Hospital
🇺🇸
Salt Lake City, Utah, United States
University of Vermont and State Agricultural College
🇺🇸
Burlington, Vermont, United States
Inova Fairfax Hospital
🇺🇸
Falls Church, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Overlake Medical Center
🇺🇸
Bellevue, Washington, United States
Valley Medical Center
🇺🇸
Renton, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
🇺🇸
Yakima, Washington, United States
United Hospital Center
🇺🇸
Bridgeport, West Virginia, United States
WVUH-Berkely Medical Center
🇺🇸
Martinsburg, West Virginia, United States
West Virginia University Healthcare
🇺🇸
Morgantown, West Virginia, United States
Camden Clark Medical Center
🇺🇸
Parkersburg, West Virginia, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸
Madison, Wisconsin, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
John Hunter Children's Hospital
🇦🇺
Hunter Regional Mail Centre, New South Wales, Australia
Sydney Children's Hospital
🇦🇺
Randwick, New South Wales, Australia
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Queensland Children's Hospital
🇦🇺
South Brisbane, Queensland, Australia
Perth Children's Hospital
🇦🇺
Perth, Western Australia, Australia
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦
Quebec, Canada
University Pediatric Hospital
🇵🇷
San Juan, Puerto Rico

Related Trials

Phase II Study of the Combination of Blinatumomab and Asciminib in Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

RecruitingPhase 2

M.D. Anderson Cancer Center

Updated 9/2/2024

Blinatumomab, Methotrexate, Cytarabine, and Ponatinib in Treating Patients With Philadelphia Chromosome-Positive, or BCR-ABL Positive, or Relapsed/Refractory, Acute Lymphoblastic Leukemia

RecruitingPhase 2

M.D. Anderson Cancer Center

Posted 8/28/2017

Updated 4/20/2025

Blinatumomab and Pembrolizumab for Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia With High Marrow Lymphoblasts

Active, Not RecruitingPhase 1

University of California, San Diego

Posted 5/19/2017

Updated 8/24/2023

Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

RecruitingPhase 2

National Cancer Institute (NCI)

Posted 3/19/2024

Updated 5/20/2025

Blinatumomab and Nivolumab With or Without Ipilimumab in Treating Patients With Poor-Risk Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

Active, Not RecruitingPhase 1

National Cancer Institute (NCI)

Posted 8/26/2016

Updated 2/4/2025

Blinatumomab in Treating Patients With B-cell Acute Lymphoblastic Leukemia With Minimal Residual Disease

Active, Not RecruitingPhase 2

M.D. Anderson Cancer Center

Posted 5/29/2015

Updated 2/24/2025

BLAM- A phase IIb study of Blinatumomab + Cytarabine (AraC) and Methotrexate in adult B-precursor Acute Lymphoblastic Leukaemia

Active, Not RecruitingPhase 2

Australasian Leukaemia and Lymphoma Group

Updated 4/15/2024

Brentuximab Vedotin and Nivolumab for the Treatment of Relapsed/Refractory Classic Hodgkin Lymphoma Previously Treated with Brentuximab Vedotin or Checkpoint Inhibitors

RecruitingPhase 2

Emory University

Posted 9/9/2021

Updated 2/27/2025

Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia

Active, Not RecruitingPhase 2

National Cancer Institute (NCI)

Posted 5/21/2014

Updated 5/14/2025

Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Myeloma

TerminatedPhase 2

Andrew Yee, MD

Posted 10/8/2019

Updated 8/21/2023

A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Recruitment & Eligibility

Study & Design

Trial Locations

Related Trials

Phase II Study of the Combination of Blinatumomab and Asciminib in Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blinatumomab, Methotrexate, Cytarabine, and Ponatinib in Treating Patients With Philadelphia Chromosome-Positive, or BCR-ABL Positive, or Relapsed/Refractory, Acute Lymphoblastic Leukemia

Blinatumomab and Pembrolizumab for Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia With High Marrow Lymphoblasts

Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

Blinatumomab and Nivolumab With or Without Ipilimumab in Treating Patients With Poor-Risk Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

Blinatumomab in Treating Patients With B-cell Acute Lymphoblastic Leukemia With Minimal Residual Disease

BLAM- A phase IIb study of Blinatumomab + Cytarabine (AraC) and Methotrexate in adult B-precursor Acute Lymphoblastic Leukaemia

Brentuximab Vedotin and Nivolumab for the Treatment of Relapsed/Refractory Classic Hodgkin Lymphoma Previously Treated with Brentuximab Vedotin or Checkpoint Inhibitors

Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia

Nivolumab, Ixazomib, Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Myeloma

Clinical Trial Alerts

Clinical Trial Alerts