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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03914625




Registration number
NCT03914625
Ethics application status
Date submitted
12/04/2019
Date registered
16/04/2019
Date last updated
25/06/2020

Titles & IDs
Public title
A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
Scientific title
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)
Secondary ID [1] 0 0
NCI-2019-02187
Secondary ID [2] 0 0
NCI-2019-02187
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
B Acute Lymphoblastic Leukemia 0 0
B Lymphoblastic Lymphoma 0 0
Down Syndrome 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Human Genetics and Inherited Disorders 0 0 0 0
Down's syndrome
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Asparaginase Erwinia chrysanthemi
Other interventions - Blinatumomab
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Cytarabine
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Doxorubicin Hydrochloride
Treatment: Drugs - Leucovorin
Treatment: Drugs - Leucovorin Calcium
Treatment: Drugs - Mercaptopurine
Treatment: Drugs - Mercaptopurine Oral Suspension
Treatment: Drugs - Methotrexate
Treatment: Drugs - Pegaspargase
Treatment: Drugs - Prednisolone
Treatment: Drugs - Prednisone
Treatment: Drugs - Thioguanine
Treatment: Drugs - Vincristine
Treatment: Drugs - Vincristine Sulfate

Active Comparator: Arm A (SR-Avg control) - Arm A: See detailed description.

Experimental: Arm B (SR-Avg experimental) - Arm B: See detailed description.

Active Comparator: Arm C (SR-High Control) - Arm C: See detailed description.

Experimental: Arm D (SR-High experimental) - Arm D See detailed description.

Experimental: B-LLy - See detailed description.

Experimental: DS B-ALL - See detailed description.

Experimental: NCI SR or HR DS B-ALL - See detailed description.


Treatment: Drugs: Asparaginase Erwinia chrysanthemi
Given IV or IM

Other interventions: Blinatumomab
Given IV

Treatment: Drugs: Cyclophosphamide
Given IV

Treatment: Drugs: Cytarabine
Given IT or IV

Treatment: Drugs: Dexamethasone
Given PO or IV

Treatment: Drugs: Doxorubicin
Given IV

Treatment: Drugs: Doxorubicin Hydrochloride
Given IV

Treatment: Drugs: Leucovorin
Given PO or IV

Treatment: Drugs: Leucovorin Calcium
Given PO or IV

Treatment: Drugs: Mercaptopurine
Given PO

Treatment: Drugs: Mercaptopurine Oral Suspension
Given PO

Treatment: Drugs: Methotrexate
Given IT or IV

Treatment: Drugs: Pegaspargase
Given IV or IM

Treatment: Drugs: Prednisolone
Given PO or IV

Treatment: Drugs: Prednisone
Given PO or IV

Treatment: Drugs: Thioguanine
Given PO

Treatment: Drugs: Vincristine
Given IV

Treatment: Drugs: Vincristine Sulfate
Given IV

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Post-Consolidation disease free survival (DFS) with addition of 2 cycle of blinatumomab - Will be assessed 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 who are negative for MRD by flow cytometry but have detectable or indeterminate MRD as measured by high throughput sequencing (HTS) at end of induction (EOI). Efficacy design and standard survival analysis methods is 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%.
Timepoint [1] 0 0
Time from end of consolidation (EOC) to first event (relapse, second malignant neoplasm, remission death) or censored at date of last contact for those who are disease-free up to 5 years
Primary outcome [2] 0 0
DFS in boys in the SR-favorable subset of SR B-ALL with or without Down syndrome (DS) - 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.
Timepoint [2] 0 0
Time from EOI to first event (relapse, second malignant neoplasm, death, treatment failure) or censored at date of last contact for those who are disease-free, up to 5 years
Secondary outcome [1] 0 0
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
Timepoint [1] 0 0
From the start of IM1 up to 2 years
Secondary outcome [2] 0 0
DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen - 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.
Timepoint [2] 0 0
5 years
Secondary outcome [3] 0 0
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
Timepoint [3] 0 0
5 years
Secondary outcome [4] 0 0
DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab - 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.
Timepoint [4] 0 0
5 years
Secondary outcome [5] 0 0
DFS of patients with localized B-lymphoblastic lymphoma (B-LLy) receiving standard risk acute lymphoblastic leukemia therapy - 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.
Timepoint [5] 0 0
5 years
Secondary outcome [6] 0 0
Neurocognitive functioning - 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).
Timepoint [6] 0 0
Baseline to 2 years after IM1
Secondary outcome [7] 0 0
Caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study - 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.
Timepoint [7] 0 0
Baseline to 2 years after IM1

Eligibility
Key inclusion criteria
- 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 patient has 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.
Minimum age
365 Days
Maximum age
31 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patient must not have secondary ALL that developed after treatment of a prior
malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior
history of transient myeloproliferative disease (TMD) are not considered to have had a
prior malignancy. They would therefore be eligible whether or not the TMD was treated
with cytarabine.

- 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 patients 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.

- Patients with known Charcot-Marie-Tooth disease.

- Patients with evidence of a MYC translocation associated with mature (Burkitt) B-cell
ALL, regardless of blast immunophenotype.

- 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
John Hunter Children's Hospital - Hunter Regional Mail Centre
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Women's and Children's Hospital-Adelaide - North Adelaide
Recruitment hospital [4] 0 0
Monash Medical Center-Clayton Campus - Clayton
Recruitment hospital [5] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2310 - Hunter Regional Mail Centre
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
5006 - North Adelaide
Recruitment postcode(s) [4] 0 0
3168 - Clayton
Recruitment postcode(s) [5] 0 0
6009 - Perth
Recruitment outside Australia
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Alabama
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Alaska
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San Juan

Funding & Sponsors
Primary sponsor type
Government body
Name
National Cancer Institute (NCI)
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This phase III trial studies how well blinatumomab works in combination with chemotherapy in
treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or
B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as
blinatumomab, may induce changes in the 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 than 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.
Trial website
https://clinicaltrials.gov/show/NCT03914625
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Sumit Gupta
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03914625