Register a trial

The ANZCTR website will be unavailable from 1pm until 3pm (AEDT) on Wednesday the 30th of October for website maintenance. Please be sure to log out of the system in order to avoid any loss of data.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

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




Registration number
NCT04546399
Ethics application status
Date submitted
11/09/2020
Date registered
14/09/2020

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
Treatment: Other - 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
Treatment: Other - 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

Treatment: Other: 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

Treatment: Other: 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
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
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Alaska
Country [3] 0 0
United States of America
State/province [3] 0 0
Arizona
Country [4] 0 0
United States of America
State/province [4] 0 0
Arkansas
Country [5] 0 0
United States of America
State/province [5] 0 0
California
Country [6] 0 0
United States of America
State/province [6] 0 0
Colorado
Country [7] 0 0
United States of America
State/province [7] 0 0
Connecticut
Country [8] 0 0
United States of America
State/province [8] 0 0
Delaware
Country [9] 0 0
United States of America
State/province [9] 0 0
District of Columbia
Country [10] 0 0
United States of America
State/province [10] 0 0
Florida
Country [11] 0 0
United States of America
State/province [11] 0 0
Georgia
Country [12] 0 0
United States of America
State/province [12] 0 0
Hawaii
Country [13] 0 0
United States of America
State/province [13] 0 0
Idaho
Country [14] 0 0
United States of America
State/province [14] 0 0
Illinois
Country [15] 0 0
United States of America
State/province [15] 0 0
Indiana
Country [16] 0 0
United States of America
State/province [16] 0 0
Iowa
Country [17] 0 0
United States of America
State/province [17] 0 0
Kentucky
Country [18] 0 0
United States of America
State/province [18] 0 0
Louisiana
Country [19] 0 0
United States of America
State/province [19] 0 0
Maine
Country [20] 0 0
United States of America
State/province [20] 0 0
Maryland
Country [21] 0 0
United States of America
State/province [21] 0 0
Massachusetts
Country [22] 0 0
United States of America
State/province [22] 0 0
Michigan
Country [23] 0 0
United States of America
State/province [23] 0 0
Minnesota
Country [24] 0 0
United States of America
State/province [24] 0 0
Mississippi
Country [25] 0 0
United States of America
State/province [25] 0 0
Missouri
Country [26] 0 0
United States of America
State/province [26] 0 0
Nebraska
Country [27] 0 0
United States of America
State/province [27] 0 0
Nevada
Country [28] 0 0
United States of America
State/province [28] 0 0
New Hampshire
Country [29] 0 0
United States of America
State/province [29] 0 0
New Jersey
Country [30] 0 0
United States of America
State/province [30] 0 0
New York
Country [31] 0 0
United States of America
State/province [31] 0 0
North Carolina
Country [32] 0 0
United States of America
State/province [32] 0 0
North Dakota
Country [33] 0 0
United States of America
State/province [33] 0 0
Ohio
Country [34] 0 0
United States of America
State/province [34] 0 0
Oklahoma
Country [35] 0 0
United States of America
State/province [35] 0 0
Oregon
Country [36] 0 0
United States of America
State/province [36] 0 0
Pennsylvania
Country [37] 0 0
United States of America
State/province [37] 0 0
Rhode Island
Country [38] 0 0
United States of America
State/province [38] 0 0
South Carolina
Country [39] 0 0
United States of America
State/province [39] 0 0
South Dakota
Country [40] 0 0
United States of America
State/province [40] 0 0
Tennessee
Country [41] 0 0
United States of America
State/province [41] 0 0
Texas
Country [42] 0 0
United States of America
State/province [42] 0 0
Utah
Country [43] 0 0
United States of America
State/province [43] 0 0
Vermont
Country [44] 0 0
United States of America
State/province [44] 0 0
Virginia
Country [45] 0 0
United States of America
State/province [45] 0 0
Washington
Country [46] 0 0
United States of America
State/province [46] 0 0
West Virginia
Country [47] 0 0
United States of America
State/province [47] 0 0
Wisconsin
Country [48] 0 0
Canada
State/province [48] 0 0
Manitoba
Country [49] 0 0
Canada
State/province [49] 0 0
Nova Scotia
Country [50] 0 0
Canada
State/province [50] 0 0
Quebec
Country [51] 0 0
Puerto Rico
State/province [51] 0 0
San Juan

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

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
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

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://grants.nih.gov/policy/sharing.htm


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04546399