A Phase 3 Trial Investigating Blinatumomab ( NSC# 765986) in Combination With Chemotherapy in Patients With Newly Diagnosed Standard Risk or Down Syndrome B-Lymphoblastic Leukemia (B-ALL) and the Treatment of Patients With Localized B-Lymphoblastic Lymphoma (B-LLy)
- Study HIC#:2000026064
- Last Updated:07/15/2021
This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with or without Down syndrome and newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma. Monoclonal antibodies, such as blinatumomab, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better then combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.
- Start Date05/26/2020
- End Date06/30/2027
Trial Purpose and Description
Primary Outcome Measures :
- Post-Consolidation disease free survival (DFS) with addition of 2 cycle of blinatumomab in patients with standard risk (SR) B-lymphoblastic leukemia (B-ALL) and higher risk features, and patients with standard risk average (SR-Avg) B-ALL [ Time Frame: 5 years ]Efficacy design and standard survival analysis methods used to detect improvement in post-Consolidation DFS due to the addition of 2 cycles of blinatumomab to standard therapy in patients with SR B-ALL and higher risk features, and patients with SR-Avg B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI), and patients with double trisomy of chromosomes 4 and 10 (DT) with MRD (flow) 0.01% - <0.1%.
- DFS in boys in the SR-favorable subset of SR B-ALL [ Time Frame: 5 years ]Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
Secondary Outcome Measures :
- DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of interim maintenance (IM)1, regardless of sex [ Time Frame: 5 years ]Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
- DFS for patients with standard-risk favorable (SR-Fav) B-ALL [ Time Frame: 5 years ]Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
- Treatment-related mortality in Down syndrome high risk (DS-high) patients after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of DI) with 3 cycles of blinatumomab [ Time Frame: 5 years ]
- DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab [ Time Frame: 5 years ]Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
- DFS of patients with localized B-lymphoblastic lymphoma receiving standard risk acute lymphoblastic leukemia therapy [ Time Frame: 5 years ]Time from end of consolidation to first event (relapse, second malignant neoplasm, remission, death) or censored at date of last contact for those who are disease-free.
- Neurocognitive functioning [ Time Frame: Baseline to 2 years after IM1 ]Compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4-< 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship (HMH), including either food, housing or energy insecurity) and non-poor families (absence of HMH).
- Caregiver burden and patient/proxy-reported symptoms among those enrolled in HMH [ Time Frame: Baseline to 2 years after IM1 ]Compare the demands and work limitations on caregivers of children with ALL receiving chemotherapy versus chemotherapy with the addition of blinatumomab and to compare the change in the demands and work limitations over time, measured by the Care of My Child with Cancer questionnaire and the Caregiver Work Limitations questionnaire during post-Induction therapy. Patient/proxy reported symptoms measured by Memorial Symptom Assessment Scale.
Other Outcome Measures:
- Adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL [ Time Frame: 5 years ]FlowSom high resolution clustering approach to identify cellular subsets and/or activation states (endophenotypes) that distinguish cases from controls. Conduct a genome-wide assessment using a case-control approach comparing those who develop grade 4-5 microbiologically documented infections (cases) compared to those who do not (controls).
- Neurocognitive, functional, and quality of life outcomes in patients with DS and ALL [ Time Frame: 5 years ]Measured by caregiver (parent/legal guardian) questionnaires.
- Prevalence of minimal marrow disease (MMD) in B-LLy [ Time Frame: 5 years ]Correlate MMD at diagnosis with outcome in patients with B-LLy.
- All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731 and MUST submit eligibility studies.
- Age at diagnosis:
- Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
- Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
- Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or without DS).
- B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment).
- B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).
- Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on a bone marrow (BM) aspirate;
- OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
- OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
- OR newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
- Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
- All patients and/or their parents or legal guardians must sign a written informed consent.
- Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy.
- With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1731.
- For patients receiving steroid pretreatment, the following additional exclusion criteria apply:
- Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
- DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV steroids within 4 weeks of diagnosis.
- B-ALL who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
- Patient must not have acute undifferentiated leukemia (AUL).
- Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be known prior to enrollment).
- Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
- Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).
- For LLy patients, the following additional exclusion criteria apply:
- T-Lymphoblastic Lymphoma.
- Morphologically unclassifiable lymphoma.
- Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
- CNS positive disease or testicular involvement.
- M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.
- Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
- Lactating females who plan to breastfeed their infants.
- Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.