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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04546399




Registration number
NCT04546399
Ethics application status
Date submitted
11/09/2020
Date registered
14/09/2020
Date last updated
18/04/2024

Titles & IDs
Public title
A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)
Scientific title
A Phase 2 Study of Blinatumomab (NSC# 765986) in Combination With Nivolumab (NSC # 748726), a Checkpoint Inhibitor of PD-1, in B-ALL Patients Aged >/= 1 to < 31 Years Old With First Relapse
Secondary ID [1] 0 0
NCI-2020-06813
Secondary ID [2] 0 0
NCI-2020-06813
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Down Syndrome 0 0
Recurrent B Acute Lymphoblastic Leukemia 0 0
Condition category
Condition code
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
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
Human Genetics and Inherited Disorders 0 0 0 0
Down's syndrome

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - 3-Dimensional Conformal Radiation Therapy
Other interventions - Blinatumomab
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Cytarabine
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Etoposide
Treatment: Drugs - Hydrocortisone Sodium Succinate
Treatment: Drugs - Leucovorin Calcium
Treatment: Drugs - Mercaptopurine
Treatment: Drugs - Methotrexate
Other interventions - Nivolumab
Treatment: Drugs - Pegaspargase
Treatment: Drugs - Thioguanine
Treatment: Drugs - Vincristine Sulfate

Experimental: Arm G (dexamethasone, blinatumomab, nivolumab,MTX) 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 and 25 of cycle 1 and days 1 and 15 of cycle 2, and 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 this cycle 1), MTX IT, cytarabine IT, or ITT IT on days 15 and 36 of cycle 2, and leucovorin calcium IV or PO q6h for 2 doses on days 2, 16 and 37 of cycle 1 and q6h for 2 doses on days 16 and 37 of cycle 2.

Experimental: Group 1, Arm A (dexamethasone, blinatumomab, MTX) - 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.

Experimental: Group 1, Arm B (dexamethasone, blinatumomab, MTX) - 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.

Experimental: Group 2, Arm C (dexamethasone, blinatumomab, MTX) - 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.

Experimental: Group 2, Arm D (dexamethasone, nivolumab, blinatumomab, MTX) - 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.

Experimental: Group 3, Arm E (dexamethasone, blinatumomab, MTX) - See Outline section

Experimental: Group 3, Arm F (dexamethasone, blinatumomab, nivolumab) - See Outline section


Treatment: Other: 3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT

Other interventions: Blinatumomab
Given IV

Treatment: Drugs: Cyclophosphamide
Given IV

Treatment: Drugs: Cytarabine
Given IT

Treatment: Drugs: Dexamethasone
Given PO or IV

Treatment: Drugs: Etoposide
Given IV

Treatment: Drugs: Hydrocortisone Sodium Succinate
Given IT

Treatment: Drugs: Leucovorin Calcium
Given PO and IV

Treatment: Drugs: Mercaptopurine
Given PO

Treatment: Drugs: Methotrexate
Given IT, PO, and IV

Other interventions: Nivolumab
Given IV

Treatment: Drugs: Pegaspargase
Given IM or IV

Treatment: Drugs: Thioguanine
Given PO

Treatment: Drugs: Vincristine Sulfate
Given IV push or via infusion
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Other interventions
Intervention code [3] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Minimal residual disease (MRD) negative second remission (Rem-2) rate with blinatumomab vs with blinatumomab + nivolumab (Group 1)
Timepoint [1] 0 0
Up to 2 cycles of therapy (each cycle = 36 days)
Primary outcome [2] 0 0
Event-free survival post-induction (Group 3)
Timepoint [2] 0 0
From date of randomization to date of relapse, disease progression, second malignancy (SMN) or death due to any cause, assessed up to 10 years after completion of enrollment.
Secondary outcome [1] 0 0
Dose-limiting toxicity
Timepoint [1] 0 0
Up to 1 cycle of therapy (each cycle = 36 days)
Secondary outcome [2] 0 0
Event-free survival post-induction (Group 2)
Timepoint [2] 0 0
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

Eligibility
Key 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
Minimum age
1 Year
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

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 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Suspended
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
4/12/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2028
Actual
Sample size
Target
550
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
John Hunter Children's Hospital - Hunter Regional Mail Centre
Recruitment hospital [2] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 0 0
Queensland Children's Hospital - South Brisbane
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
2031 - Randwick
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
4101 - South Brisbane
Recruitment postcode(s) [5] 0 0
6009 - Perth
Recruitment outside Australia
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United States of America
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Alabama
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Alaska
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North Carolina
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Oregon
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Pennsylvania
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Rhode Island
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Tennessee
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Manitoba
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Puerto Rico
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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 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04546399
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Stacy L Cooper
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/ct2/show/NCT04546399