Study of Blinatumomab With or Without Nivolumab for Relapsed B-ALL
This study is for patients aged 1 to 30 years old with B-cell acute lymphoblastic leukemia (B-ALL) that has returned (relapsed). This includes patients with Down Syndrome. It compares two treatments: blinatumomab alone versus blinatumomab combined with nivolumab. Blinatumomab is an antibody that targets and helps kill cancer cells. Nivolumab is a medicine that may boost your immune system. The main goal is to see if adding nivolumab improves how long patients live without the cancer returning (event-free survival). The study plans to enroll 461 participants.
- Study design
- This is an interventional study comparing blinatumomab alone to blinatumomab with nivolumab, with a planned enrollment of 461 participants.
- What's involved
- You would undergo procedures like blood, urine, and cerebrospinal fluid collection, and bone marrow aspiration. You may also receive 3-Dimensional Conformal Radiation Therapy and Asparaginase Erwinia chrysanthemi.
- Compensation
- Not stated in the trial record.
- Follow-up
- Participants will be followed for event-free survival for up to 10 years after completing enrollment.
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NCT04546399
A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)
Recruiting
PHASE2Ages 1–30InterventionalTreatmentNational Cancer Institute (NCI)Government-funded
~461 participants
Updated 2026-06-12 on ClinicalTrials.gov
What's tested:3-Dimensional Conformal Radiation TherapyAsparaginase Erwinia chrysanthemiBiospecimen CollectionBlinatumomabBone Marrow AspirationBone Marrow Biopsy
At a glance
Recruiting sites
164 of 225 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Minimal residual disease (MRD) negative second remission (Rem-2) rate with blinatumomab vs with blinatumomab + nivolumab (Group 1)
Measured over Up to 2 cycles of therapy (each cycle = 36 days)
+2 more outcomes measured
Conditions
Where it's being run
225 sites across 58 statesNevada23
California22
Michigan22
Florida13
Texas13
New York12
Ohio8
Washington7
Study leadership
- Stacy L Cooper · PRINCIPAL_INVESTIGATOR · Children's Oncology Group
Who to contact
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Do you actually qualify for this trial?
Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.
Eligibility criteria
Inclusion
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
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 or ABL class Ph-like B-ALL (i.e. rearrangements involving ABL1, ABL2, CSF1R or PDGFRB and predicted to be sensitive to imatinib or dasatinib)
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
Patients with DS patients with known non-hematopoietic, non-CNS/testicular extramedullary disease (i.e., chloromatous disease) are not eligible
Note: Group 3 and 4 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
What this trial measures
- 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, 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, 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.