A Phase 2 Study of Blinatumomab in Combination with Nivolumab, a Checkpoint Inhibitor of PD-1, in B-ALL Patients Aged < 1 to < 31 Years Old with First Relapse.
- To compare rate of minimal residual disease (MRD) negative second remission after up to two cycles of Reinduction with blinatumomab vs. blinatumomab/nivolumab in Group 1 patients aged; 1 to < 31 years old with first relapse of CD19+ B-ALL.
- To compare EFSPI (EFS post-Induction) between Consolidation with blinatumomab vs. blinatumomab/nivolumab in Group 3 patients aged; 1 to <31 years old with first relapse of CD19+ B-ALL.
- To evaluate the safety and tolerability of blinatumomab/nivolumab in patients aged 1 to < 31 years old with first relapse of CD19+ B ALL.
- To compare EFSPI between blinatumomab vs. blinatumomab/nivolumab in Group 2 patients aged; 1 to < 31 years old with first relapse of CD19+ B-ALL. In Group 1 patients, compare EFS between blinatumomab monotherapy and blinatumomab/nivolumab arms as compared to similar patients treated on the predecessor trial AALL1331.
In Group 1 patients: compare toxicity as defined by Grade 3 or greater adverse events during the first cycle of blinatumomab or blinatumomab/nivolumab to similar patients treated with Block 1 of cytotoxic chemotherapy on the predecessor trial AALL1331.
In Group 2 patients with MRD; 0.1% after VXLD, compare MRD negative second remission (Rem-2) rate after the first cycle of immunotherapy between blinatumomab monotherapy and blinatumomab/nivolumab arms.
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.
Opdivo (Nivolumab)
- Rutgers Cancer Institute of New Jersey
- RWJBarnabas Health
- Newark Beth Israel Medical Center
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
- Radiation therapy (RT): >= 3 months must have elapsed if prior RT. This
includes any patient requiring urgent radiation to any sites of extramedullary
disease prior to enrollment (e.g. retinal/optic nerve involvement)
- Hematopoietic stem cell transplant (HSCT): 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 (steroid and/or hydroxyurea only) is permissible
- Group 1 and Down syndrome patients who received pre-enrollment therapy and
have a white blood count (WBC) >= 30,000/ul at the time of enrollment must
receive protocol specified cytoreductive therapy with vincristine and
dexamethasone, and no "washout" is required
- Group 1 and Down syndrome patients 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/gender 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)
- 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. 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 1 and DS patients with known non-hematopoietic, non-CNS/testicular
extramedullary disease (i.e., chloromatous disease) are not eligible
- Note: Group 2 and 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. Men receiving nivolumab and who are sexually
active with WOCBP must continue contraception for 7 months after the last dose of
nivolumab
- Lactating females are not eligible unless they agree not to 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
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.