PRIMARY OBJECTIVES:
I. To compare event free survival post reinduction (EFS PR) between blinatumomab vs.
blinatumomab/nivolumab in Group 4 patients aged ≥ 1 to <31 years old with first relapse
of CD19+ B ALL.
II. To compare EFS PR (EFS post-reinduction) between consolidation with blinatumomab vs.
blinatumomab/nivolumab in Group 3 patients aged >= 1 to < 31 years old with first relapse
of CD19+ B ALL.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of blinatumomab/nivolumab in patients aged >=
1 to < 31 years old with first relapse of CD19+ B ALL.
EXPLORATORY OBJECTIVES:
I. In Group 4 patients, compare EFS PR between blinatumomab monotherapy and
blinatumomab/nivolumab arms as compared to similar patients treated on the predecessor
trial AALL1331.
II. In Group 4 patients, compare toxicity as defined by grade 3 or greater adverse events
during the first cycle of blinatumomab or blinatumomab/nivolumab.
III. In Group 4 patients, compare MRD negative second remission (Rem-2) rate after the
first cycle of immunotherapy between blinatumomab monotherapy and blinatumomab/nivolumab
arms.
IV. 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.
V. With each Group, perform subset analyses of EFS and overall survival (OS) based on
features including degree of marrow disease at relapse, age, sex, body mass index,
cytogenetics, site(s) of relapse, percent peripheral blasts at relapse and absolute
lymphocyte count at first relapse.
OUTLINE:
Patients >= 18 years old with marrow +/- extramedullary (EM) relapse of any duration
after initial diagnosis, or patients < 18 years old with marrow +/- EM relapse < 24
months after initial diagnosis are assigned to Group 1. Patients < 18 years old with
marrow +/- EM relapse >= 24 months from initial diagnosis, or all isolated extramedullary
(IEM) relapses >= 1 to < 31 years old are assigned to Groups 2-3 re-induction. Patients
with DS are assigned to Arm G. NOTE: Patients in Group 1 and DS patients with white blood
cells (WBC) >= 30,000/uL, CNS 2/3 disease, or testicular disease must first receive 1 of
3 pre-immunotherapy treatments.
Starting with amendment 4C (9/19/2024), patients with DS are assigned to group 3 or 4.
Patients < 18 years with bone marrow first relapse ≥ 36 months from initial diagnosis
with MRD <0.1% after VXLD reinduction or with isolated CNS/testicular extramedullary
relapse occurring ≥ 18 months from initial diagnosis with MRD <0.1% after VXLD
reinduction are assigned to group 3. Patients who do not meet criteria for group 3 will
be assigned to group 4. Patients with Down syndrome ≥ 1 to < 31 years of age with first
bone marrow relapse of B ALL are assigned to arm G.
PRE-IMMUNOTHERAPY TREATMENT FOR PATIENTS WITH WBC >= 30,000/uL (CLOSED TO ACCRUAL
9/19/2024 EXCEPT FOR ARM G) : Patients receive methotrexate (MTX) intrathecally (IT) or
cytarabine IT or intrathecal triple therapy (ITT) consisting of MTX, hydrocortisone
sodium succinate, and cytarabine IT at the time of diagnostic lumbar puncture (LP) or on
day 1 (if intrathecal therapy is given with relapse diagnostic LP < 7 days prior to the
start of protocol therapy). Patients also receive dexamethasone intravenously (IV) or
orally (PO) twice daily (BID) on days 1-5, vincristine sulfate via infusion or IV IV push
over 1 minute on day 1. Patients with DS also receive leucovorin calcium PO or IV every 6
hours (q6h) for 2 doses on day 2 or at 24 and 30 hours after each IT administration.
Patients should proceed to the next cycle when CNS 1 and no testicular disease is
present, no sooner than Day 8 and no later than Day 15.
PRE-IMMUNOTHERAPY TREATMENT FOR CNS 2/3 DISEASE (CLOSED TO ACCRUAL 9/19/2024 EXCEPT FOR
ARM G): Patients receive MTX IT or cytarabine IT twice weekly (Q2W) for 5-7 doses or
Intrathecal Triple Therapy (ITT) IT Q2W for 3-4 doses until patient is CNS 1. Patients
with DS also receive leucovorin calcium PO or IV q6h for 2 doses at 24 and 30 hours after
each IT administration. Patients should proceed to the next cycle when CNS 1 and no
testicular disease is present, no sooner than Day 15 and no later than Day 24.
PRE-IMMUNOTHERAPY TREATMENT FOR TESTICULAR DISEASE(CLOSED TO ACCRUAL 9/19/2024 EXCEPT FOR
ARM G): Patients receive MTX IT, cytarabine IT, or ITT IT on days 1 and 15 (day 1 may be
omitted if intrathecal therapy is given with relapse diagnostic LP < 7 days prior to the
start of protocol therapy). Patients with DS also receive leucovorin calcium PO or IV q6h
for 2 doses on days 2 and 16 or at 24 and 30 hours after each IT administration. Males
with testicular disease at relapse undergo radiation once daily (QD) for a total of 12
fractions over 12 days. Patients should proceed to the next cycle when CNS 1 and no
testicular disease is present, no sooner than Day 15 and no later than Day 22.
GROUP 1 (CLOSED TO ACCRUAL 9/19/2024): Patients are randomized to Arm A or Arm B.
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.
ARM B: 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.
GROUPS 2-4 VXLD REINDUCTION: Patients receive vincristine sulfate via infusion or IV push
over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV on days 1-14, doxorubicin
hydrochloride IV over 1-15 minutes on day 1, MTX IT on days 1, 8, and 29 (day 1 IT may be
omitted if intrathecal therapy is given with relapse diagnostic LP < 7 days prior to the
start of this cycle) (days 8 and 29 for CNS 1 patients at relapse only), pegaspargase
intramuscularly (IM) or IV over 1-2 hours on days 2 and 16 or calasparagase IV over 1-2
hours on day 2 (for patients ≤ 22 years), cytarabine IT on days 4 and 11 (CNS 2 patients
at relapse only), then Q2W until 3 consecutive samples are clear of blasts, and ITT IT on
days 8, 15, 22, and 29 (CNS 3 patients at relapse only). Treatment continues in the
absence of disease progression or unacceptable toxicity.
GROUP 2 (CLOSED TO ACCRUAL 9/19/2024): The following patients are randomized to Arm C or
Arm D: 1) >= 1 to < 31 years old, IEM relapse < 18 months from diagnosis, regardless of
MRD after Re-Induction. 2) < 18 years old with marrow relapse >= 24 to < 36 months from
diagnosis regardless of MRD after Re-Induction, 3) >= 1 to < 31 years old, IEM relapse >=
18 months, and MRD >= 0.1% after Re-Induction, 4) < 18 years old with marrow relapse >=
36 months, and MRD >= 0.1% after Re-Induction.
ARM C: 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 MTX IT on days 1 and 15 of
cycles 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal MTX is given < 7 days
prior to the start of cycle 1 ). 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.
ARM D: 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.
GROUP 3: Patients are randomized to Arm E or Arm F.
ARM E:
IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1
only, blinatumomab IV via continuous infusion on days 1-28, and MTX IT on days 1 and 15
(day 1 may be omitted from cycle 1 if intrathecal therapy is given < 7 days prior to the
start of this cycle). Immunotherapy cycles 1-2 alternate with Consolidation cycles 1-2.
CONSOLIDATION: Patients receive dexamethasone PO or IV on days 1-5, methotrexate IV, over
24 hours, on days 8 and 22, methotrexate IT on days 8 and 22 (CNS 1/2 at relapse only) or
ITT IT on days 8 and 22 (CNS 3 at relapse only).
INTENSIFICATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine
sulfate IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42,
methotrexate IV over 24 hours on days 8 and 22, cytarabine IV, over 3 hours on days 43
and 44, asaparaginase erwinia recombiant IM or crisantaspase/asparaginase erwinia IM or
IV over 1-2 hours on day 44, methotrexate IT on days 1 and 43 (CNS 1/2 at relapse only)
or ITT IT on days 1 and 43 (CNS 3 at relapse only).
IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days
1-28, and MTX IT on days 1 and 15 (CNS 1/2 at relapse only) or ITT IT on days 1 and 15
(CNS 3 at relapse only).
MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61,
vincristine sulfate IV push over 1 minute or via infusion on days 1, 29, and 57,
mercaptopurine PO on days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT
IT on day 1 (CNS 3 patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43,
50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years from the start of
Re-Induction therapy in the absence of disease progression or unacceptable toxicity.
MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS ONLY): Beginning between the first and
second cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7
and 15-21, vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and
15, and pegaspargase IM or IV over 1-2 hours or calaspargase IV over 1-2 hours on day 1.
Patients with CNS 3 and isolated CNS relapse undergo cranial radiation in the form of
3-dimensional (D)-conformal radiation therapy (CRT) over 5 days per week for a total of
10 treatments.
ARM F:
IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1
only, blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes
on days 11 of cycle 1 and on days 1 of cycles 2 and 3, and MTX IT on days 1 and 15 (CNS
1/2 patients at relapse only)(day 1 may be omitted from cycle 1 if intrathecal therapy is
given with < 7 days prior to the start of this cycle) or , ITT IT on day 1 (CNS 3
patients at relapse only) (day 1 may be omitted from cycle 1 if intrathecal therapy is
given with < 7 days prior to the start of this cycle). Immunotherapy cycles 1-2 alternate
with Consolidation cycles 1-2.
CONSOLIDATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine
sulfate IV push over 1 minute or via infusion on day 1, methotrexate IV, over 24 hours,
on days 8 and 22, methotrexate IT on days 8 and 22 (CNS 1/2 at relapse only) or ITT IT on
days 8 and 22 (CNS 3 at relapse only).
INTENSIFICATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine
sulfate IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42,
methotrexate IV over 24 hours on days 8 and 22, cytarabine IV, over 3 hours on days 43
and 44, asaparaginase erwinia recombiant IM or crisantaspase/asparaginase erwinia IM or
IV over 1-2 hours on day 44, methotrexate IT on days 1 and 43 (CNS 1/2 at relapse only)
or ITT IT on days 1 and 43 (CNS 3 at relapse only).
IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days
1-28, nivolumab IV over 30 minutes on days 1 and 15 and MTX IT on days 1 and 15.
MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61,
vincristine sulfate IV push over 1 minute or via infusion on days 1, 29, and 57,
mercaptopurine PO on days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT
IT on day 1 (CNS 3 patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43,
50, 57, 64, 71, 78. Treatment repeats every 12 weeks for 2 years from the start of
Re-Induction therapy in the absence of disease progression or unacceptable toxicity.
MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS): Beginning between the first and second
cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and
15-21, vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15,
and pegaspargase IM or IV over 1-2 hours or calaspargase IV over 1-2 hours on day 1.
Patients with CNS 3 and isolated CNS relapse undergo cranial radiation in the form of
3-dimensional (D)-conformal radiation therapy (CRT) over 5 days per week for a total of
10 treatments.
GROUP 4: Patients are randomized to arm H or arm I.
ARM H: Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only,
blinatumomab IV via continuous infusion on days 1-28 and MTX IT on days 1 of cycle 1 only
and days 15 and 36 ( for patients with CNS1/2 at relapse only) or ITT on day 1 of cycle 1
only and days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may
be omitted from cycle 1 if intrathecal therapy is given with < 7 days prior to the start
of this cycle). Cycles repeat every 36 days for up to 2 cycles in the absence of disease
progression or unacceptable toxicity.
ARM I: Patients receive dexamethasone PO or IV on day 1 and 8 of cycle 1 only,
blinatumomab IV via continuous infusion on days 1-28, nivolumab IV, over 30 minutes on
day 11 of cycle 1 and day 3 of cycle 2 and MTX IT on days 1 of cycle 1 only and days 15
and 36 ( for patients with CNS 1/2 at relapse only) or ITT on day 1 of cycle 1 only and
days 15 and 36 (for patients with CNS 3 at relapse only) (day 1 IT therapy may be omitted
from cycle 1 if intrathecal therapy is given with < 7 days prior to the start of this
cycle). Cycles repeat every 36 days for up to 2 cycles in the absence of disease
progression or unacceptable toxicity.
ARM G (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 of cycle 1 and day 3 of cycle 2, and MTX IT (for patients with CNS 1/2 at
relapse only) or ITT on day 1 of cycle 1 only and days 15 and 36 (for patients with CNS 3
at relapse only) (day 1 IT therapy may be omitted from cycle 1 if intrathecal therapy is
given with < 7 days prior to the start of this cycle). Cycles repeat every 37 days for up
to 2 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo lumbar puncture, bone marrow biopsy and aspiration, and collection of
blood, urine and cerebrospinal fluid throughout the study.
After completion of study treatment, patients are followed up every 3 months for 1 year.