Clofarabine or High-Dose Cytarabine and Pegaspargase in Children With ALL

Sponsor

Universitätsklinikum Hamburg-Eppendorf (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01228331

Collaborator

(none)

745

Enrollment

Locations

Arms

170

Duration (Months)

53.2

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Amsacrine Drug: Clofarabine Drug: Cyclophosphamide Drug: Cytarabine Drug: Daunorubicin hydrochloride Drug: Dexamethasone Drug: Doxorubicin hydrochloride Drug: Etoposide phosphate Drug: Mercaptopurine Drug: Methotrexate Drug: Methylprednisolone Drug: Pegaspargase Drug: Thioguanine Drug: Vincristine sulfate Radiation: Whole-brain radiation therapy	Phase 2/Phase 3

Detailed 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

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

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

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

745 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2010

Actual Primary Completion Date :

Dec 1, 2019

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I intensification (cytarabine) LR-S patients receive HD cytarabine IV 4 x 3 g over 12 hours daily on days 29-31 and pegaspargase IV over 2 hours on days 31, 52, and 80. LR-I and precursor B-cell ALL HR-S and HR-I patients receive HD cytarabine IV 2.500 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. Followed by standard consolidation therapy regarding to stratification containing: methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL	Drug: Amsacrine one block amsacrine together with etoposide and methylprednisolone for very high risk patients Drug: Cyclophosphamide together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction Drug: Cytarabine part of different chemotherapy blocks in consolidation and reinduction Drug: Dexamethasone part of reinduction therapy Drug: Etoposide phosphate part of different chemotherapy blocks Drug: Methotrexate part of different chemotherapy blocks Drug: Methylprednisolone part of different chemotherapy blocks Drug: Pegaspargase part of different chemotherapy blocks Drug: Thioguanine part of different chemotherapy blocks Drug: Vincristine sulfate part of intravenous chemotherapy Radiation: Whole-brain radiation therapy patients with initial cns involvement receive cranial irradiation
Active Comparator: Arm II intensification (clofarabine) LR-S patients receive clofarabine* IV 5 x 40 mg over 2 hours every day on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80. LR-I and precursor B-cell ALL HR-S and HR-I patients receive clofarabine* IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and 108. Followed by standard consolidation therapy regarding to stratification containing: methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL	Drug: Amsacrine one block amsacrine together with etoposide and methylprednisolone for very high risk patients Drug: Clofarabine one block clofarabine with Asparaginase for MRD positive patients after induction Drug: Cyclophosphamide together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction Drug: Daunorubicin hydrochloride part of induction and reinduction therapy Drug: Dexamethasone part of reinduction therapy Drug: Etoposide phosphate part of different chemotherapy blocks Drug: Methotrexate part of different chemotherapy blocks Drug: Methylprednisolone part of different chemotherapy blocks Drug: Pegaspargase part of different chemotherapy blocks Drug: Thioguanine part of different chemotherapy blocks Drug: Vincristine sulfate part of intravenous chemotherapy Radiation: Whole-brain radiation therapy patients with initial cns involvement receive cranial irradiation
Active Comparator: Arm III reinduct.(doxorubicin hydrochl.) LR-S patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1 and 8. LR-I, HR-S and HR-I Patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1, 8, 22, and 29. Followed by standard reinduction and maintenance therapy containing: cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate	Drug: Cyclophosphamide together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction Drug: Cytarabine part of different chemotherapy blocks in consolidation and reinduction Drug: Dexamethasone part of reinduction therapy Drug: Doxorubicin hydrochloride part of reinduction therapy Drug: Mercaptopurine part of different chemotherapy blocks Drug: Methotrexate part of different chemotherapy blocks Drug: Pegaspargase part of different chemotherapy blocks Drug: Vincristine sulfate part of intravenous chemotherapy
Active Comparator: Arm IV reinduct.(daunorubicin hydrochl.) LR-S patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1 and 8. LR-I, HR-S and HR-I Patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1, 8, 22, and 29. Followed by standard reinduction and maintenance therapy containing: cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate	Drug: Cyclophosphamide together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction Drug: Cytarabine part of different chemotherapy blocks in consolidation and reinduction Drug: Daunorubicin hydrochloride part of induction and reinduction therapy Drug: Dexamethasone part of reinduction therapy Drug: Mercaptopurine part of different chemotherapy blocks Drug: Methotrexate part of different chemotherapy blocks Drug: Pegaspargase part of different chemotherapy blocks Drug: Vincristine sulfate part of intravenous chemotherapy

Outcome Measures

Primary Outcome Measures

Safety and efficacy of clofarabine combined with pegaspargase (phase II) [at day 21 after chemotherapy]
minimal residual disease diagnostic, toxicity form

Secondary Outcome Measures

Incidence of infectious complications after administration of daunorubicin hydrochloride vs doxorubicin hydrochloride [at the end of reinduction therapy]
toxicity form

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

diagnosis after the first and before the 18th birthday AND confirmed diagnosis of acute B-precursor or or T-cell leukemia AND parents or guardians/patients give consent for inclusion in the study and transmission of data AND if none of exclusion criteria is accomplished

Exclusion criteria:

BCR/ABL rearrangement positive OR prior cytostatic treatment lasting > 7 days or prior treatment with cytostatic drugs other than vincristine, daunorubicin and prednisone OR prior severe illnesses which make treatment per the protocol impossible from the outset (BUT trisomy 21 is not an exclusion criterion) OR absence of the baseline data required for assignment to a risk group in accordance with the protocol (BUT patients for whom the MRD value could not be determined for technical reasons will be treated as protocol patients) OR the disease is a secondary malignancy or relapse OR death before the start of treatment

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Krankenanstalten Gilead gCmbH Neurochirurgische Klinik	Bielefeld	Germany	33617
2	Klinikum Bremen-Mitte	Bremen	Germany	D-28205
3	Universitaetsklinikum Duesseldorf	Duesseldorf	Germany	D-40225
4	Klinik und Poliklinik Fuer Kinder-und Jugendmedizin - Universitaetsklinikum Greifswald	Greifswald	Germany	17487
5	University Medical Center Hamburg - Eppendorf	Hamburg	Germany	D-20246
6	Clinic for Bone Marrow Transplantation and Hematology and Oncology	Idar-Oberstein	Germany	D-55743
7	Klinikum Krefeld GmbH	Krefeld	Germany	D-47805
8	Universitaets - Kinderklinik	Leipzig	Germany	D-04317
9	Johannes Gutenberg University	Mainz	Germany	D-55101
10	Dr. von Haunersches Kinderspital der Universitaet Muenchen	Munich	Germany	D-80337
11	Staedtisches Krankenhaus Muenchen - Harlaching	Munich	Germany	D-81545
12	Klinik St. Hedwig-Kinderklinik	Regensburg	Germany	93049
13	Dr. Horst-Schmidt-Kliniken	Wiesbaden	Germany	D-65199
14	Helios Kliniken Wuppertal University Hospital	Wuppertal	Germany	D-42283