Trial Information

A Randomized Multi-Center Treatment Study (COALL 08-09) to Improve the Survival of Children With Acute Lymphoblastic Leukemia on Behalf of the German Society of Pediatric Hematology and Oncology

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.