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

Condition(s) targeted: Leukemia

Intervention: 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 (Drug); Whole-brain radiation therapy (Radiation)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Universitätsklinikum Hamburg-Eppendorf

Official(s) and/or principal investigator(s):
Martin Horstmann, MD, Principal Investigator, Affiliation: Universitätsklinikum Hamburg-Eppendorf

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.

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 design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Safety and efficacy of clofarabine combined with pegaspargase (phase II)

Cytotoxic efficacy of clofarabine compared with high-dose (HD) cytarabine in combination with pegaspargase (phase III)

Incidence of infectious complications after administration of daunorubicin hydrochloride vs doxorubicin hydrochloride

Secondary outcome:

Safety profiles of clofarabine and pegaspargase vs HD cytarabine and pegaspargase

Efficacy of clofarabine and pegaspargase and HD cytarabine and pegaspargase, in terms of minimal-residual disease (MRD) vs methotrexate, cyclophosphamide, and asparaginase in study COALL-07-03

Impact of MRD-based stratification in COALL-09 on overall survival and event-free survival in a historical comparison of previous COALL studies

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 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.

Minimum age: 1 Year. Maximum age: 17 Years. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) or T-cell ALL* after

October 1st 2009

- No B-cell ALL NOTE: *Patients with non-Hodgkin lymphoma of the T-cell or B-cell

precursor type are included in the observation group.

- Meets 1 of the following risk group criteria:

- Low-risk (LR) disease meeting all of the following criteria:

- WBC < 25/nL at diagnosis

- Age ≥ 1 to < 10 years

- Common ALL or precursor B-cell ALL

- Complete remission on day 29 (after induction therapy)

- No 11q23 rearrangement

- No hypodiploid chromosome number

- High-risk (HR) disease meeting any of the following criteria:

- WBC ≥ 25/nL at diagnosis

- Age ≥ 10 years

- Progenitor B-cell ALL or T-cell ALL

- No complete remission on day 29

- 11q23 rearrangement

- Hypodiploid chromosome number (< 45 chromosomes)

- Must meet 1 of the following criteria regarding minimal-residual disease (MRD):

- LR disease after induction (on day 29):

- LR-reduced (LR-R): MRD negative

- LR-standard (LR-S): MRD positive but < 10^-3 or no evaluable MRD results

- LR-intensified (LR-I): MRD ≥ 10^-3

- HR disease after induction and intensification ????? (on day 29 and/or day 43):

- HR-reduced (HR-R):

- T-cell ALL: MRD < 10^-3 on day 29

- Precursor B-cell ALL: MRD negative on day 29

- HR-standard (HR-S):

- T-cell ALL: MRD ≥ 10^-3 on day 29 and < 10^-3 on day 43

- Precursor B-cell ALL: MRD positive on day 29 but < 10^-3 or no

evaluable MRD results

- HR-intensified (HR-I):

- T-cell ALL: MRD ≥ 10^-3 on day 43

- Precursor B-cell ALL: MRD ≥ 10^-3 on day 29

- Must be under treatment at 1 of the participating hospitals

- No disease that is a secondary malignancy or relapsed

- After induction, patients with translocation t(9;22) will receive treatment as part

of the European Study on Philadelphia-positive leukemia (EsPhALL)

- bcr-abl-positive patients will be assigned and treated according to different

protocols PATIENT CHARACTERISTICS:

- No prior severe illness that makes treatment on this study impossible from the outset

- Trisomy 21 (Down syndrome) allowed

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior cytostatic treatment lasting > 7 days

- No prior treatment with drugs other than vincristine sulfate, daunorubicin

hydrochloride, and prednisone

Krankenanstalten Gilead gCmbH Neurochirurgische Klinik, Bielefeld 33617, Germany; Recruiting
Contact Person, Phone: 49-521-144-2728

Klinikum Bremen-Mitte, Bremen D-28205, Germany; Recruiting
Contact Person, Phone: 49-421-497-5413

Universitaetsklinikum Duesseldorf, Duesseldorf D-40225, Germany; Recruiting
Contact Person, Phone: 49-211-81-17662

Klinik und Poliklinik Fuer Kinder-und Jugendmedizin - Universitaetsklinikum Greifswald, Greifswald 17487, Germany; Recruiting
Contact Person, Phone: 49-3834-86-6321

University Medical Center Hamburg - Eppendorf, Hamburg D-20246, Germany; Recruiting
Contact Person, Phone: 49-407-4105-2580, Email: horstmann@uke.uni-hamburg.de

Clinic for Bone Marrow Transplantation and Hematology and Oncology, Idar-Oberstein D-55743, Germany; Recruiting
Contact Person, Phone: 49-6781-66-1582

Klinikum Krefeld GmbH, Krefeld D-47805, Germany; Recruiting
Contact Person, Phone: 49-2151-322-375

Universitaets - Kinderklinik, Leipzig D-04317, Germany; Recruiting
Contact Person, Phone: 49-341-9726-113

Johannes Gutenberg University, Mainz D-55101, Germany; Recruiting
Contact Person, Phone: 49-6131-17-2642

Dr. von Haunersches Kinderspital der Universitaet Muenchen, Munich D-80337, Germany; Recruiting
Contact Person, Phone: 49-89-5160-2843

Staedtisches Krankenhaus Muenchen - Harlaching, Munich D-81545, Germany; Recruiting
Contact Person, Phone: 49-89-6210-2720

Klinik St. Hedwig-Kinderklinik, Regensburg 93049, Germany; Recruiting
Contact Person, Phone: 49-941-2080-493

Dr. Horst-Schmidt-Kliniken, Wiesbaden D-65199, Germany; Recruiting
Contact Person, Phone: 49-611-43-2564

Helios Kliniken Wuppertal University Hospital, Wuppertal D-42283, Germany; Recruiting
Contact Person, Phone: 49-202-896-2444

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 2010
Last updated: January 28, 2015