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

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.