Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03959085 |
| Other study ID # |
AALL1732 |
| Secondary ID |
NCI-2019-02845AA |
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
October 31, 2019 |
| Est. completion date |
March 31, 2030 |
Study information
| Verified date |
April 2024 |
| Source |
Children's Oncology Group |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This phase III trial studies whether inotuzumab ozogamicin added to post-induction
chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves
outcomes. This trial also studies the outcomes of patients with mixed phenotype acute
leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without
inotuzumab ozogamicin. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab,
linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in
a targeted way and delivers calicheamicin to kill them. Other drugs used in the chemotherapy
regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin,
methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and
pegaspargase or calaspargase pegol 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. This trial will also study the outcomes of patients with mixed phenotype acute
leukemia (MPAL) and disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk
ALL chemotherapy.
The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard
of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic
Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy:
Induction and Consolidation. This part will collect information on the leukemia, as well as
the effects of the initial treatment, to classify patients into post-consolidation treatment
groups. On the second part of this study, patients with HR B-ALL will receive the remainder
of the chemotherapy cycles (interim maintenance I, delayed intensification, interim
maintenance II, maintenance), with some patients randomized to receive inotuzumab. The
patients that receive inotuzumab will not receive part of delayed intensification. Other aims
of this study include investigating whether treating both males and females with the same
duration of chemotherapy maintains outcomes for males who have previously been treated for an
additional year compared to girls, as well as to evaluate the best ways to help patients
adhere to oral chemotherapy regimens. Finally, this study will be the first to track the
outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed
Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.
Description:
PRIMARY OBJECTIVE:
I. To compare in a randomized manner the 5-year disease-free survival (DFS) for children and
young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with
modified Berlin-Frankfurt-Munster (mBFM) chemotherapy without delayed intensification (DI)
part 2, but with the addition of two blocks of inotuzumab ozogamicin, versus those treated
with full mBFM chemotherapy backbone including DI Part 2 without the addition of inotuzumab
ozogamicin.
SECONDARY OBJECTIVES:
I. To describe the 5-year DFS for a favorable risk subset of National Cancer Institute (NCI)
HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate
(HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of
IM regardless of sex.
II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the
mBFM chemotherapy backbone in HR B-ALL including toxicity experienced during phases of
therapy subsequent to inotuzumab ozogamicin.
III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute
leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi
intravenous (IV) methotrexate without leucovorin rescue plus pegaspargase or calaspargase
pegol (C-MTX).
IV. To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell
lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM
phase with C-MTX.
EXPLORATORY OBJECTIVES:
I. To describe the therapy administered, disease response, and survival outcomes of patients
with MPAL who come off protocol therapy due to poor disease response to ALL therapy either
during Induction, at end of induction (EOI), or at end of consolidation (EOC).
II. To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis
and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy.
III. To determine the impact of proposed adherence-enhancing interventions on adherence to
oral 6-mercaptopurine in patients with ALL.
OUTLINE: All patients receive the same Induction and Consolidation chemotherapy. Patients
with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or
III. Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm
V.
All patients with B-ALL receive Induction and Consolidation therapy:
INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system
(CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also
receive vincristine intravenously (IV) on days 1, 8, 15, and 22, daunorubicin IV over 1-15
minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or
pegaspargase intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29 (and on days
15 and 22 for CNS3 patients). Patients < 10 years old receive dexamethasone orally (PO) twice
daily (BID) or IV on days 1-14; patients >= 10 years old receive prednis(ol)one PO BID or IV
on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or
unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of
age.
CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39,
mercaptopurine PO once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8,
15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive
vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2
hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of
disease progression or unacceptable toxicity. Additionally, patients with testicular disease
at diagnosis that does not resolve by the end of induction will undergo radiation therapy
over 12 once daily fractions. Calaspargase pegol can only be given to patients less than 22
years of age.
POST-CONSOLIDATION THERAPY: After Consolidation, based on clinical features and response,
patients with B-ALL are designated as HR-Fav or HR B-ALL. Patients with HR-Fav B-ALL are
assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL
and B-LLy are assigned to therapy arms (Arms IV and V) that are identical to Arm II. Patients
that are < 10 years, have CNS1, no testicular leukemia, with favorable cytogenetics (ETV6
RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours of steroids in the two weeks prior
to diagnosis, and EOI MRD < 0.01% are assigned to Arm I. Patients with HR B-ALL who are
surface CD22 positive at diagnosis and have MRD < 0.01% by the end of Consolidation, are
randomized to either Arm II or III.
ARM I: HR-FAV B-ALL (Patients that are < 10 years, have CNS1 status, no testicular leukemia,
with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies [4 and 10]), =< 24 hours
of steroids in the two weeks prior to diagnosis, and EOI MRD < 0.01%)
INTERIM MAINTENANCE: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose
methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4,
17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and
methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease
progression or unacceptable toxicity.
DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over
1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV
over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed
Intensification) continues for 9 weeks in the absence of disease progression or unacceptable
toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase
or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and
II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or
unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of
age.
MAINTENANCE: Patients receive methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for
subsequent cycles. Patients also receive vincristine IV on day 1, prednisolone PO BID or IV
on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO on days 8, 15, 22, 29
(excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat every 12 weeks for up
to 2 years in the absence of disease progression or unacceptable toxicity.
Patients with HR B-ALL who have MRD < 0.01% by the end of Consolidation, and leukemic blasts
positive for surface CD22 at diagnosis are randomized to Arm II or Arm III.
ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1,
15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29 and 43, leucovorin
PO or IV on days 3-4, 17-18, 31-32, 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42,
and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the
absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over
1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV
over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed
Intensification) continues for 9 weeks in the absence of disease progression or unacceptable
toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase
or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and
II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or
unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of
age.
INTERIM MAINTENANCE II: Patients receive vincristine on days 1, 11, 21, 31 and 41,
methotrexate IV over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41,
methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on
days 2 and 22 (pegaspargase) or 23 (calaspargase) or pegaspargase IM on days 2 and 22.
Treatment continues for 8 weeks in the absence of disease progression or unacceptable
toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
ARM III: HR B-ALL (EXPERIMENTAL) INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive
inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1.
Treatment continues for 4 weeks in the absence of disease progression or unacceptable
toxicity.
INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29 and 43, high dose
methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4,
17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, and
methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease
progression or unacceptable toxicity.
DELAYED INTENSIFICATION (Part I): Patients receive methotrexate IT on day 1, dexamethasone PO
BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over
1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV
over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed
Intensification) continues for 5 weeks in the absence of disease progression or unacceptable
toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15.
Treatment continues for 4 weeks in the absence of disease progression or unacceptable
toxicity.
INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41,
methotrexate IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or 23
(calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the
absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given
to patients less than 22 years of age.
ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV on day 1, prednisolone
PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22,
29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71 and 78, and methotrexate IT on days 1
(and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every
12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
Patients with CNS3 disease undergo cranial radiation therapy over 10 fractions during the
first 4 weeks.
ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also
receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV on
days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase
or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on
days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive
dexamethasone PO BID or IV on days 1-14; patients >= 10 years old receive prednisolone PO BID
or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or
unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of
age.
CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO
on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22
for CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or
calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment
continues for 8 weeks in the absence of disease progression or unacceptable toxicity.
Patients with testicular disease at diagnosis that does not resolve by the end of induction
will and continued evidence of testicular disease at end of induction undergo testicular
radiation over 12 once-daily fractions. Calaspargase pegol can only be given to patients less
than 22 years of age.
ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also
receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV on
days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase
or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on
days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients < 10 years old receive
dexamethasone PO BID or IV on days 1-14; patients >= 10 years old receive prednisolone PO BID
or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or
unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of
age.
CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO
on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22
CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase
pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks
in the absence of disease progression or unacceptable toxicity. Patients with testicular
disease at diagnosis that does not resolve by the end of induction will and continued
evidence of testicular disease at end of induction undergo testicular radiation therapy over
12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years
of age.
ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: Patients
receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on
days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46,
methotrexate IT on days 1 and 29 and mercaptopurine PO QD on days 1-14, 15-28, 29-42, and
43-56. Treatment continues for 9 weeks in the absence of disease progression or unacceptable
toxicity.
DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO
BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over
1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV
over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed
Intensification) continues for 9 weeks in the absence of disease progression or unacceptable
toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on
day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and
36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43
and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day
43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the
absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given
to patients less than 22 years of age.
INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41,
methotrexate IV or infusion over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41,
methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on
days 2 and 22 (pegaspargase) or (calaspargase) 23 or pegaspargase IM on days 2 and 22.
Treatment continues for 8 weeks in the absence of disease progression or unacceptable
toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
MAINTENANCE: Patients receive vincristine IV on days 1, prednisolone PO BID or IV on days
1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in
cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days 1 (and 29 of
cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks
for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients
with CNS3 disease at diagnosis undergo cranial radiation therapy for 10 fractions over 4
weeks.
Patients undergo blood sample collection and bone marrow aspiration and biopsy on study.
B-LLy patients undergo computed tomography (CT), magnetic resonance imaging (MRI), positron
emission tomography (PET), and/or bone scan on study.
After completion of study treatment, patients are followed up at 4 weeks, then every 3 months
for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.
