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

NCT ID: NCT01228331

Last Updated: 2024-12-11

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

745 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-10-31

Study Completion Date

2024-11-20

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Leukemia

Keywords

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childhood acute lymphoblastic leukemia untreated childhood acute lymphoblastic leukemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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

Group Type ACTIVE_COMPARATOR

Amsacrine

Intervention Type DRUG

one block amsacrine together with etoposide and methylprednisolone for very high risk patients

Cyclophosphamide

Intervention Type DRUG

together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction

Cytarabine

Intervention Type DRUG

part of different chemotherapy blocks in consolidation and reinduction

Dexamethasone

Intervention Type DRUG

part of reinduction therapy

Etoposide phosphate

Intervention Type DRUG

part of different chemotherapy blocks

Methotrexate

Intervention Type DRUG

part of different chemotherapy blocks

Methylprednisolone

Intervention Type DRUG

part of different chemotherapy blocks

Pegaspargase

Intervention Type DRUG

part of different chemotherapy blocks

Thioguanine

Intervention Type DRUG

part of different chemotherapy blocks

Vincristine sulfate

Intervention Type DRUG

part of intravenous chemotherapy

Whole-brain radiation therapy

Intervention Type RADIATION

patients with initial cns involvement receive cranial irradiation

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

Group Type ACTIVE_COMPARATOR

Amsacrine

Intervention Type DRUG

one block amsacrine together with etoposide and methylprednisolone for very high risk patients

Clofarabine

Intervention Type DRUG

one block clofarabine with Asparaginase for MRD positive patients after induction

Cyclophosphamide

Intervention Type DRUG

together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction

Daunorubicin hydrochloride

Intervention Type DRUG

part of induction and reinduction therapy

Dexamethasone

Intervention Type DRUG

part of reinduction therapy

Etoposide phosphate

Intervention Type DRUG

part of different chemotherapy blocks

Methotrexate

Intervention Type DRUG

part of different chemotherapy blocks

Methylprednisolone

Intervention Type DRUG

part of different chemotherapy blocks

Pegaspargase

Intervention Type DRUG

part of different chemotherapy blocks

Thioguanine

Intervention Type DRUG

part of different chemotherapy blocks

Vincristine sulfate

Intervention Type DRUG

part of intravenous chemotherapy

Whole-brain radiation therapy

Intervention Type RADIATION

patients with initial cns involvement receive cranial irradiation

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

Group Type ACTIVE_COMPARATOR

Cyclophosphamide

Intervention Type DRUG

together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction

Cytarabine

Intervention Type DRUG

part of different chemotherapy blocks in consolidation and reinduction

Dexamethasone

Intervention Type DRUG

part of reinduction therapy

Doxorubicin hydrochloride

Intervention Type DRUG

part of reinduction therapy

Mercaptopurine

Intervention Type DRUG

part of different chemotherapy blocks

Methotrexate

Intervention Type DRUG

part of different chemotherapy blocks

Pegaspargase

Intervention Type DRUG

part of different chemotherapy blocks

Vincristine sulfate

Intervention Type DRUG

part of intravenous chemotherapy

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

Group Type ACTIVE_COMPARATOR

Cyclophosphamide

Intervention Type DRUG

together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction

Cytarabine

Intervention Type DRUG

part of different chemotherapy blocks in consolidation and reinduction

Daunorubicin hydrochloride

Intervention Type DRUG

part of induction and reinduction therapy

Dexamethasone

Intervention Type DRUG

part of reinduction therapy

Mercaptopurine

Intervention Type DRUG

part of different chemotherapy blocks

Methotrexate

Intervention Type DRUG

part of different chemotherapy blocks

Pegaspargase

Intervention Type DRUG

part of different chemotherapy blocks

Vincristine sulfate

Intervention Type DRUG

part of intravenous chemotherapy

Interventions

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Amsacrine

one block amsacrine together with etoposide and methylprednisolone for very high risk patients

Intervention Type DRUG

Clofarabine

one block clofarabine with Asparaginase for MRD positive patients after induction

Intervention Type DRUG

Cyclophosphamide

together wit MTX and ASP in consolidation and together with cytarabine and 6-TG in reinduction

Intervention Type DRUG

Cytarabine

part of different chemotherapy blocks in consolidation and reinduction

Intervention Type DRUG

Daunorubicin hydrochloride

part of induction and reinduction therapy

Intervention Type DRUG

Dexamethasone

part of reinduction therapy

Intervention Type DRUG

Doxorubicin hydrochloride

part of reinduction therapy

Intervention Type DRUG

Etoposide phosphate

part of different chemotherapy blocks

Intervention Type DRUG

Mercaptopurine

part of different chemotherapy blocks

Intervention Type DRUG

Methotrexate

part of different chemotherapy blocks

Intervention Type DRUG

Methylprednisolone

part of different chemotherapy blocks

Intervention Type DRUG

Pegaspargase

part of different chemotherapy blocks

Intervention Type DRUG

Thioguanine

part of different chemotherapy blocks

Intervention Type DRUG

Vincristine sulfate

part of intravenous chemotherapy

Intervention Type DRUG

Whole-brain radiation therapy

patients with initial cns involvement receive cranial irradiation

Intervention Type RADIATION

Eligibility Criteria

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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
Minimum Eligible Age

1 Year

Maximum Eligible Age

17 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Universitätsklinikum Hamburg-Eppendorf

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Martin Horstmann, MD

Role: PRINCIPAL_INVESTIGATOR

Universitätsklinikum Hamburg-Eppendorf

Locations

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Krankenanstalten Gilead gCmbH Neurochirurgische Klinik

Bielefeld, , Germany

Site Status

Klinikum Bremen-Mitte

Bremen, , Germany

Site Status

Universitaetsklinikum Duesseldorf

Düsseldorf, , Germany

Site Status

Klinik und Poliklinik Fuer Kinder-und Jugendmedizin - Universitaetsklinikum Greifswald

Greifswald, , Germany

Site Status

University Medical Center Hamburg - Eppendorf

Hamburg, , Germany

Site Status

Clinic for Bone Marrow Transplantation and Hematology and Oncology

Idar-Oberstein, , Germany

Site Status

Klinikum Krefeld GmbH

Krefeld, , Germany

Site Status

Universitaets - Kinderklinik

Leipzig, , Germany

Site Status

Johannes Gutenberg University

Mainz, , Germany

Site Status

Dr. von Haunersches Kinderspital der Universitaet Muenchen

Munich, , Germany

Site Status

Staedtisches Krankenhaus Muenchen - Harlaching

Munich, , Germany

Site Status

Klinik St. Hedwig-Kinderklinik

Regensburg, , Germany

Site Status

Dr. Horst-Schmidt-Kliniken

Wiesbaden, , Germany

Site Status

Helios Kliniken Wuppertal University Hospital

Wuppertal, , Germany

Site Status

Countries

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Germany

Related Links

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https://www.kinderkrebsinfo.de/health_professionals/clinical_trials/pohkinderkrebsinfotherapiestudien/coall_08_09/index_eng.html

Clinical trial summary from the information portal of the German Society of Paediatric Oncology and Haematology (GPOH)

Other Identifiers

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2009-012758-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CDR0000686545

Identifier Type: -

Identifier Source: org_study_id