Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01228331 |
| Other study ID # |
CDR0000686545 |
| Secondary ID |
2009-012758-18 |
| Status |
Active, not recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
October 2010 |
| Est. completion date |
December 2024 |
Study information
| Verified date |
January 2024 |
| Source |
Universitätsklinikum Hamburg-Eppendorf |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. Giving more than once
drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses
high-energy x-rays to kill cancer cells. It is not yet known whether giving clofarabine or
high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin
hydrochloride or doxorubicin hydrochloride is more effective in treating young patients with
acute lymphoblastic leukemia.
PURPOSE: This randomized phase II/III trial is studying the side effects of giving
clofarabine compared with giving high-dose cytarabine, pegaspargase, and combination
chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride and to see
how well it works in treating young patients with T-cell acute lymphoblastic leukemia or
precursor B-cell acute lymphoblastic leukemia.
Description:
OBJECTIVES:
Primary
- To investigate the safety and efficacy of clofarabine combined with pegaspargase in
patients with high-risk acute lymphoblastic leukemia during the first phase of the
study. (Phase II)
- To investigate, in terms of minimal-residual disease (MRD), the cytotoxic efficacy of
clofarabine compared with high-dose cytarabine in combination with pegaspargase in these
patients. (Phase III)
- To compare the incidence of infectious complications after the administration of
daunorubicin hydrochloride versus doxorubicin hydrochloride during reinduction.
Secondary
- To compare the safety profiles of clofarabine and pegaspargase versus high-dose
cytarabine and pegaspargase in these patients.
- To compare, in terms of MRD, the efficacy of clofarabine and pegaspargase and high-dose
cytarabine and pegaspargase, respectively, versus methotrexate, cyclophosphamide, and
asparaginase in study GER-COALL-07-03, the historical control group (retrospective
comparison).
- To determine the influence of MRD-based stratification in COALL-09 on overall survival
and event-free survival in a historical comparison of previous COALL studies.
OUTLINE: This is a multicenter, sequential phase II/III study. Patients are stratified to low
risk (LR) or high risk (HR) depending on peripheral white blood cell count on diagnosis, age
on diagnosis, and immunological subtype. Patients undergo 2 randomizations (1 during
intensification and 1 during reinduction) in the study.
- Preliminary treatment: All patients receive daunorubicin hydrochloride IV over 24 hours
on day -7 and methotrexate intrathecally (IT) once on day -9, -8, or -7.
- Induction: All patients receive vincristine IV on days 1, 8, 15, and 22; daunorubicin
hydrochloride IV over 24 hours on days 1, 8, and 15; and oral prednisone 3-4 times daily
on days 1-28.
Patients are assessed for minimal-residual disease (MRD) status after induction phase.
Patients not in remission on day 29 are treated off study. Patients with LR disease are
further stratified to LR-reduced (LR-R), LR-standard (LR-S), and LR-intensified (LR-I)
groups; patients with HR disease are further stratified to HR-reduced (HR-R), HR-standard
(HR-S), and HR-intensified (HR-I) groups. Patients in the LR-R and HR-R groups do not undergo
randomization during study.
- Intensification (randomization 1): Patients receive therapy according to risk and
disease subtypes. Some patients in different risk group are randomized* to receive
high-dose (HD) cytarabine and pegaspargase or clofarabine and pegaspargase.
- LR-R and LR-S: Patients receive medium-high-dose (mHD) methotrexate IV over 24
hours on days 50, 64, and 78; etoposide phosphate IV over 1-2 hours and cytarabine
IV over 1 hour on day 66; oral mercaptopurine on days 50-56 and 78-120; oral
thioguanine on days 64-70; and methotrexate IT on days 29, 50, 64, and 78. Patients
in LR-S group who still have a detectable MRD load on day 29 are randomized
(randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs.
clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3
hours twice daily on days 29-31 and pegaspargase IV over 2 hours on days 31,
52, and 80.
- Arm II (clofarabine and pegaspargase) Patients receive clofarabine IV over 2
hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80.
- LR-I and precursor B-cell acute lymphoblastic leukemia (ALL) HR-S and HR-I:
Patients receive cyclophosphamide IV over 30 minutes on days 50 and 64; mHD IV over
24 hours on days 51, 65, 78, and 92; etoposide phosphate IV over 1-2 hours and
cytarabine IV over 1 hour on days 80 and 94; oral mercaptopurine on days 64-70 and
92-98; oral thioguanine on days 78-84; and methotrexate IT on days 29, 51, 65, 78,
and 92. All precursor B-cell ALL patients with a detectable MRD load on day 29 and
T-cell ALL patients with an MRD load ≥ 10³ on day 29 are randomized* (randomization
1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and
pegaspargase.
- Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3
hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours
on days 31, 53, 67, and 108.
- Arm II (clofarabine and pegaspargase) Patients receive clofarabine* IV over 2
hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and
108.
- NOTE: *In phase II, all patients with an MRD load of ≥ 104 (on day 29) receive
clofarabine and pegaspargase without randomization.
- T-cell ALL HR (HR-R, HR-S, and HR-I): Patients receive cyclophosphamide IV over 30
minutes on days 29 and 64; mHD methotrexate IV over 24 hours on days 30, 65, 78,
and 92; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on days
80 and 94; oral mercaptopurine on days 64-70 and 92-98; oral thioguanine on days
78-84; and methotrexate IT on days 30, 43, 65, 78, and 92. Patients in HR-S and
HR-I group are randomized* (randomization 1) to 1 of 2 arms to receive cytarabine
and pegaspargase vs. clofarabine and pegaspargase.
- Arm I (cytarabine and pegaspargase): Patients receive HD cytarabine IV over 3
hours twice daily on days 43-45 and 106-108 and pegaspargase IV over 2 hours
on days 32, 45, 67, and 108.
- Arm II (clofarabine and pegaspargase): Patients receive clofarabine IV over 2
hours on days 43-47 and pegaspargase IV over 2 hours on days 32, 47, 67, and
108.
Patients in HR-I group also receive amsacrine IV over 4 hours and etoposide phosphate IV over
2 hours on days 127 and 128, methylprednisolone IV over 30 minutes on days 127-130, and
methotrexate IT on day 127, at the end of intensification.
NOTE: *In phase II, all patients with an MRD load of ≥ 103 (on day 43) receive clofarabine
and pegaspargase without randomization.
- CNS therapy: All patients with initial CNS involvement undergo cranial radiotherapy for
a total of 12 or 18 Gy. HR patients (precursor B-cell ALL with initial WBC count ≥
200/nL and T-cell ALL with initial WBC count ≥ 100/nL) with no initial CNS involvement
also undergo cranial radiotherapy for a total of 12 Gy, beginning 2-3 weeks after the
last dose of HD cytarabine or clofarabine. LR patients and HR patients (precursor B-cell
ALL with initial WBC count < 200/nL and T-cell ALL with initial WBC count < 100/nL) with
no initial CNS involvement do not receive initial cranial radiotherapy. At the beginning
of CNS therapy, before cranial radiotherapy, HR-I patients receive vincristine IV on day
1; doxorubicin hydrochloride IV over 24 hours on day 1; oral dexamethasone 3 times daily
on days 1-7; and pegaspargase IV over 2 hours on day 7.
All patients receive interim therapy comprising 3 doses (2 in week 1 and 1 in week 3) of
methotrexate IT and oral mercaptopurine daily during the 4 weeks between intensification and
reinduction.
- Reinduction (randomization 2): Patients undergo reinduction immediately after completion
of interim therapy. Patients in LR-S, LR-I, HR-S, and HR-I groups are randomized to 1 of
2 arms (doxorubicin hydrochloride vs. daunorubicin hydrochloride)
- LR-S: Patients receive vincristine IV on days 1 and 8, oral dexamethasone on days
1-14, pegaspargase IV over 2 hours on day 9, cyclophosphamide IV over 30 minutes on
day 22, cytarabine IV or intramuscularly (IM) on days 23-26, oral thioguanine on
days 22-28, and methotrexate IT on days 1, 22, and 36.
- Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride
IV over 24 hours on days 1 and 8.
- Arm IV (daunorubicin hydrochloride): Patients receive daunorubicin
hydrochloride IV over 24 hours on days 1 and 8.
- LR-R and HR-R: Patients are not randomized. They receive vincristine IV on days 1
and 8, oral dexamethasone on days 1-14, pegaspargase IV over 2 hours on day 8, and
methotrexate IT on days 1 and 15.
- LR-I, HR-S, and HR-I: Patients receive vincristine IV on days 1, 8, 22, and 29;
oral dexamethasone twice daily on days 1-14 and 22-35; cyclophosphamide IV over 30
minutes on days 43 and 57; cytarabine IV or IM on days 43-46 and 57-60; oral
thioguanine on days 43-49 and 57-63; and methotrexate IT* on days 1, 22, and 43.
- Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride
IV over 24 hours on days 1, 8, 22, and 29.
- Arm IV (daunorubicin hydrochloride) Patients receive daunorubicin
hydrochloride IV over 24 hours on days 1, 8, 22, and 29.
NOTE: *Patients who underwent cranial radiotherapy do not receive methotrexate IT.
- Maintenance: Beginning 2-3 weeks after reinduction, all patients receive oral
mercaptopurine daily and oral methotrexate weekly for 2 years. Except for LR-R and HR-R,
patients also receive pegaspargase IV over 2 hours every 3 weeks for 3 doses. Patients
who have not undergone CNS radiotherapy receive methotrexate IT at 3, 6, and 9 months.
Blood and bone marrow samples may be collected periodically for research studies.
After completion of study treatment, patients are followed monthly for 1 year, every 3 months
for 2 years, every 6 months for 2 years, and then annually for 5 years.
PROJECTED ACCRUAL: A total of 41 high-risk patients will be accrued for phase II, 296
patients for the first randomization (phase III), and 396 patients for the second
randomization will be accrued for this study.
