A Phase III Randomized Trial for Newly Diagnosed High Risk B-Lymphoblastic Leukemia (B-ALL) Testing Clofarabine (IND# 73789, NSC# 606869) in the Very High Risk Stratum

Location:

Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

PRIMARY OBJECTIVES: I. To determine if the administration of post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance (IM) high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of children with high-risk (HR) acute lymphoblastic leukemia (ALL) compared to age-adjusted intrathecal (IT) methotrexate (MTX). II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide-containing regimen (Experimental Arm 1) or the clofarabine + cyclophosphamide + etoposide-combination regimen (Experimental Arm 2) will improve the 4-year DFS of children, adolescents, and young adults with very high-risk (VHR) ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). III. To determine, in a randomized fashion, if the cyclophosphamide + etoposide + clofarabine-containing combination regimen (Experimental Arm 2) will improve the 4-year DFS of children, adolescents, and young adults with VHR-ALL compared to the cyclophosphamide + etoposide combination regimen (Experimental Arm 1). SECONDARY OBJECTIVES: I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR-ALL. II. To determine the toxicity and tolerability of Experimental Arms 1 and 2 compared to the Control Arm in children, adolescents, and young adults with VHR-ALL. III. To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-IMIDM and reduced vincristine/steroid pulse frequency and enhanced supportive care in children with Down syndrome (DS) and HR-ALL will result in a >= 65% 5-year DFS and < 10% Induction mortality, and to gather clinical and biologic data that will facilitate further study to improve outcomes for this biologically and clinically unique patient subgroup. IV. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR-ALL. V. To determine if the reduction of minimal-residual disease (MRD) from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR-ALL receiving Experimental Arms 1 and/or 2 compared to the Control Arm. VI. To estimate overall survival (OS) rates both overall and by regimen for HR-ALL and VHR-ALL patients. VII. To determine if peripheral blood absolute lymphocyte count (ALC) at day 29 of Induction is predictive of DFS in children, adolescents, and young adults with HR-ALL. VIII. To determine the incidence and prognostic significance of recently discovered recurrent genomic lesions, including high cytokine receptor-like factor 2 (CRLF2) expression, CRLF2-activating genomic lesions, janus kinase (JAK) mutations, and IKAROS family zinc finger 1 (Ikaros) (IKZF1) mutations/deletions, in patients treated on this trial. IX. To determine the prognostic significance of molecular risk classifiers using Low Density Array (LDA) Taqman cards. X. To define the frequency of occurrence of key adverse events across all patient subgroups of HR-ALL in order to provide data for linked correlative biology studies that seek to develop biomarkers predictive of patients at risk for such events, including the following specific events: Grade 2 or higher (CNS hemorrhage, pancreatitis, osteonecrosis [ON], and seizure), Grade 3 or higher (GI bleed, encephalopathy, neuropathy, allergic reaction, ileus, mucositis/stomatitis, hyperbilirubinemia, and thrombosis), and all grades (transient ischemic attacks, strokes). XI. To define the differences in the burden of therapy between HR-ALL and VHR-ALL when treated on the various arms of this study by collecting and comparing the total number of days admitted to the hospital. XII. To determine the incidence of ON, defined by magnetic resonance (MR) imaging, and to characterize the natural history of clinically silent ON in children, adolescents, and young adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for development of ON. XIII. To determine if the prevalence of cognitive deficits measured by CogState, in children (ages 6 to 11 years) with HR- and VHR-ALL at 1 year off therapy, is significantly higher than the normative population (> 14%) in the following domains: working memory, executive function, visual motor, processing speed, and visual attention. XIV. To compare the drug delivery of vincristine, pegaspargase, and methotrexate during Induction, Consolidation, Delayed Intensification, and Interim Maintenance II in 16-30 year olds treated on the control arm of the VHR study to that of adolescents and young adults (AYAs) with ALL treated with the same therapy on the C10403 adult cooperative group trial. OUTLINE: This is a multicenter study. Patients are stratified according to Down syndrome (no vs yes). Induction therapy for ALL patients without Down syndrome (35 days): Patients receive induction chemotherapy comprising cytarabine intrathecally (IT) on day 1; vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 (plus days 15 and 22 for CNS3). Patients are stratified according to National Cancer Institute (NCI) ALL risk criteria (high-risk or standard-risk vs very high-risk). High-risk or standard-risk ALL: Patients are randomized to 1 of 2 treatment arms. Consolidation therapy (56 days): Arm I HR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-4 and 29-42, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy (RT) once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Arm II HR-ALL C: Patients receive intrathecal triple therapy (ITT) comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients also receive consolidation therapy as patients in arm I HR-ALL C. Patients with testicular leukemia also undergo RT as in arm I HR-ALL C. Interim maintenance therapy (63 days): Arm I HR-ALL IM: Patients receive interim maintenance (IM) therapy comprising vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Arm II HR-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in arm I HR-ALL IM. Delayed intensification therapy (56 days): Arm I HR-ALL DI: Patients receive delayed intensification (DI) therapy comprising vincristine sulfate IV over 1 hour on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. Arm II HR-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in arm I HR-ALL DI. Maintenance therapy: Arm I HR-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV over 1 minute on days 1, 29, and 57; methotrexate IT on days 1 (also day 29 of courses 1-4) ; prednisone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. Arm II HR-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance therapy as in arm I HR-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. Very high-risk ALL: Patients are randomized to 1 of 3 treatment arms. Consolidation therapy part 1 (days 1-28): In all arms, patients receive cyclophosphamide IV over 30-60 minutes on day 1; cytarabine IV or SC on days 1-4 and 8-11; mercaptopurine PO on days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS patients): vincristine sulfate IV over 1 minute on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Consolidation therapy part 2 (days 29-57): Arm A VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; mercaptopurine PO on days 29-42; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm B VHR-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm C VHR-ALL C: Patients receive clofarabine IV over 2 hours on days 29-33 and consolidation therapy as in arm B VHR-ALL C. Interim Maintenance I (63 days): In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Delayed Intensification part 1 (days 1-28): In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day 1; and pegaspargase IV over 1-2 hours on day 4. Delayed Intensification part 2 (days 29-57): Arm A VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; thioguanine PO on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm B VHR-ALL DI: Patients receive DI therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 1-2 hours on days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Arm C VHR-ALL DI: Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy as in arm II B VHR-ALL DI. Interim Maintenance II (56 days): In all arms, patients receive vincristine sulfate IV over 1 minute and methotrexate IV on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Maintenance therapy: Patients with CNS3 disease at diagnosis undergo RT once daily over 4 weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not receive RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. High-risk ALL patients with Down syndrome: Patients are stratified according to response to induction therapy (days 1-14) (rapid early responders [RER; M1 day 15 bone marrow] vs slow early responders [SER; M2/M3 day 15 bone marrow]). Induction therapy (days 1-14): All patients receive cytarabine IT on day 1; vincristine sulfate IV over 1 minute on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 1-14, pegaspargase IV over 1-2 hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Induction therapy (day 15-29): RER patients receive induction therapy comprising vincristine sulfate IV over 1 minute on days 15 and 22; dexamethasone PO BID or prednisone PO BID on days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and leucovorin calcium PO on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). SER patients receive daunorubicin hydrochloride IV over 1-15 minutes on day 15 and induction therapy as RER patients. Consolidation therapy (56 days): All patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO on days 1-14 and 29-42; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on days 1, 8, 15, and 22; and leucovorin calcium PO on days 3-4, 10-11, 17-18, and 24-25. Patients with continuing clinical evidence of testicular leukemia undergo RT once daily, 5 days a week, for approximately 2½ weeks (12 fractions total). Interim maintenance therapy (63 days): Patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO on days 1-56; and methotrexate IT on days 1 and 29. Delayed intensification therapy: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 15-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on days 1, 29, and 36; and leucovorin calcium PO on days 3-4, 31-32 and 38-39. Maintenance therapy: Patients with CNS3 disease undergo RT once daily, 5 days a week, for 2 weeks (10 fractions total). Patients receive vincristine sulfate IV over 1 minute on day 1; prednisone PO BID or IV on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for CNS3 patients who did not receive RT). Treatment repeats every 12 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo peripheral blood and bone marrow collection for correlative studies. Patients who are at least 10 years old have MRIs during Consolidation, Maintenance, and End of therapy and blood draws during Consolidation, Delayed Intensification, and Interim Maintenance II (VHR-ALL only). Patients may also undergo neurocognitive assessment during consolidation therapy, periodically during maintenance therapy, and at 1 year after completion of study therapy. After completion of study therapy, patients are followed up periodically for 10 years.

Who is eligible to participate?

Inclusion Criteria: - Patients must be enrolled on AALL08B1 prior to enrollment on AALL1131 - White Blood Cell Count (WBC) Criteria - Age 1-9.99 years: WBC >= 50 000/μL - Age 10-30.99 years: Any WBC - Age 1-30.99 years: Any WBC with: - Testicular leukemia - CNS leukemia (CNS3) - Steroid pretreatment - Patients must have newly diagnosed B lymphoblastic leukemia (2008 WHO classification) (also termed B-precursor acute lymphoblastic leukemia); patients with Down syndrome are also eligible - Eligibility criteria for the Incidence and Natural History of Osteonecrosis study - Patients must be 10 years of age or greater at the time of B-ALL diagnosis, enrolled on AALL1131 - Patients with Down syndrome are not eligible - Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study - Patients must be aged 6 to 11 years at time of B-ALL diagnosis, enrolled on AALL1131 - Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available) - Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation) - Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli - Patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the HR B-ALL stratum of this study at the end of Induction: - Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with Day 8 PB minimal residual disease (MRD) >= 1% and Day 29 BM MRD < 0.01% - With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any Day 8 PB MRD and Day 29 BM MRD > 0.01% - Both NCI SR and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria, will be eligible for the HR stratum - Patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the VHR B-ALL stratum of this study at the end of Induction: - iAMP21 - Mixed-lineage leukemia (MLL) rearrangement - Hypodiploidy (n < 44 chromosomes and/or a deoxyribonucleic acid [DNA] index < 0.81) - Induction Failure (M3 BM at Day 29) - Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with Day 29 BM MRD > 0.01% - Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction: - Day 29 MRD >= 0.01% - MLL rearrangement - Hypodiploidy (n< 45 chromosomes and/or DNA index < 0.81) - DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction Failure (M3 BM Day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131) - All patients and/or their parents or legal guardians must sign a written informed consent - All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met Exclusion Criteria: - With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving prior steroid therapy may be eligible for AALL1131 - Patients with BCR-ABL1 fusion (not eligible for post-Induction therapy on this study; non-DS patients may be eligible to enroll in AALL1122 or successor COG Ph+ ALL trial by Day 15 Induction) - DS HR B-ALL patients with Induction failure or BCR-ABL1 - Direct bilirubin > 1.5 x upper limit of normal (ULN) for age - Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) > 3 x upper limit of normal (ULN) for age - Lipase > 2.0 x upper limit of normal (ULN) for age - Creatinine clearance or radioisotope GFR < 70 mL/min/1.73 m^2 - A serum creatinine based on age/gender as follows: - 1 month to < 6 months = 0.4 (male) and 0.4 (female) - 6 months to < 1 year = 0.5 (male) and 0.5 (female) - 1 to < 2 years = 0.6 (male) and 0.6 (female) - 2 to < 6 years = 0.8 (male) and 0.8 (female) - 6 to < 10 years = 1 (male) and 1 (female) - 10 to < 13 years = 1.2 (male) and 1.2 (female) - 13 to < 16 years = 1.5 (male) and 1.4 (female) - >= 16 years = 1.7 (male) and 1.4 (female) - VHR B-ALL patients with known Hepatitis B or C infection or history of cirrhosis at the time of post-Induction randomization - Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs - Lactating females are not eligible unless they have agreed not to breastfeed their infant - Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained - Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

Last updated:

6/30/2014

NCT ID:

NCT01406756

IRB Number:

11-007833