Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

  • STATUS
    Recruiting
  • End date
    Jun 30, 2028
  • participants needed
    700
  • sponsor
    Children's Oncology Group
Updated on 28 January 2021
cancer
calcium
stem cell transplantation
lymphoid leukemia
imatinib
cyclophosphamide
philadelphia chromosome
acute leukemia
methotrexate
cytarabine
filgrastim
vincristine
ejection fraction
direct bilirubin
hydrocortisone
cell transplantation
leukemia
shortening fraction
glomerular filtration rate
adult t-cell leukemia/lymphoma
mercaptopurine
etoposide
daunorubicin
prednisolone
pegaspargase
b-cell acute lymphoblastic leukemia
induction therapy
dexamethasone
doxorubicin
anthracyclines
combination chemotherapy
leucovorin
conjugated bilirubin
anthracycline
thioguanine
therapeutic hydrocortisone
left ventricular fractional shortening

Summary

This randomized phase III trial studies how well imatinib mesylate and combination chemotherapy work in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia. Imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving imatinib mesylate and combination chemotherapy may work better in treating patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

Description

PRIMARY OBJECTIVE:

I. To compare disease-free survival (DFS) of standard risk pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone.

SECONDARY OBJECTIVES:

I. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients.

II. To determine event-free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

III. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms.

IV. To evaluate event free survival (EFS) and overall survival (OS) of all enrolled participants.

V. To evaluate OS in SR patients. VI. To evaluate OS in high risk (HR) patients.

EXPLORATORY OBJECTIVES:

I. To describe the toxicities associated with post-HSCT administration of imatinib.

II. To evaluate the long-term toxicities in SR patients treated with chemotherapy plus imatinib (no transplant), overall and between both randomized arms.

III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy.

IV. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome.

V. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.

VI. To determine prognostic significance of IKZF1 gene aberrations and deletions.

VII. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.

VIII. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and methotrexate) during the maintenance phase in SR Ph+ ALL patients.

IX. To identify factors associated with poor adherence. X. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).

XI. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence.

OUTLINE

INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14.

INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29.

INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 15-18, and 22-25, and methotrexate IT on days 8 and 22.

POST-INDUCTION THERAPY: Patients with standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C.

ARM A:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 5, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase IV over 1-2 hours or IM on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high dose cytarabine IV over 3 hours on days 1-2, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase IV over 1-2 hours or IM on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours or IM on day 8 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase IV over 1-2 hours or IM on day 8 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO on days 1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.

ARM B:

INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63, vincristine sulfate IV over 1 minute and 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 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 1, 8, and 15, and pegaspargase IV over 1-2 hours or IM on day 4 in the absence of disease progression or unexpected toxicity.

DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, 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 or IM on day 43 in the absence of disease progression or unexpected toxicity.

INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22 in the absence of disease progression or unexpected toxicity.

MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1 and 2). Cycles repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity.

ARM C:

CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium, high dose cytarabine, and pegaspargase as in Arm A Consolidation Block 1, and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity.

CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity.

HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A.

POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up every year for 3 years.

Details
Condition childhood ALL, Minimal Residual Disease, T-cell acute lymphoblastic leukemia, B Acute Lymphoblastic Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Childhood Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia, Philadelphia Chromosome Positive, B-cell Acute Lymphoblastic Leukemia, Lymphocytic Leukemia, Acute, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, BCR-ABL1 Fusion Protein Expression, acute lymphoblastic leukemia, leukemia, acute lymphoblastic, pro b, acute lymphoid leukaemia, acute lymphocytic leukemia, acute lymphoblastic leukemia (all)
Treatment cyclophosphamide, methotrexate, laboratory biomarker analysis, questionnaire administration, Leucovorin calcium, filgrastim, cytarabine, etoposide, vincristine sulfate, ifosfamide, allogeneic hematopoietic stem cell transplantation, Imatinib Mesylate, Methylprednisolone, Dexamethasone, MESNA, doxorubicin, Pegaspargase, Mercaptopurine, Prednisolone, Thioguanine, daunorubicin hydrochloride, therapeutic hydrocortisone, Dexrazoxane Hydrochloride
Clinical Study IdentifierNCT03007147
SponsorChildren's Oncology Group
Last Modified on28 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 2 yrs and 21 yrs?
Gender: Male or Female
Do you have any of these conditions: Philadelphia Chromosome Positive or Mixed Phenotype Acute Leukemia or childhood ALL or Untreated Childhood Acute Lymphoblastic Leukemia or T-cell acut...?
Do you have any of these conditions: B-cell Acute Lymphoblastic Leukemia or acute lymphoblastic leukemia (all) or childhood ALL or B Acute Lymphoblastic Leukemia or BCR-ABL1 Fusion Protei...?
Do you have any of these conditions: Minimal Residual Disease or Mixed Phenotype Acute Leukemia or B Acute Lymphoblastic Leukemia or Lymphocytic Leukemia, Acute or acute lymphoid leukaemi...?
Do you have any of these conditions: acute lymphoblastic leukemia (all) or pro b or B Acute Lymphoblastic Leukemia or childhood ALL or acute lymphocytic leukemia or B Acute Lymphoblastic ...?
For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled
For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe
In addition, laboratory reports detailing evidence of BCR-ABL1 fusion must be submitted for rapid central review within 72 hours of study enrollment
Newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or reverse transcriptase (RT)-PCR
Patient must have previously started induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
Patient has not received more than 14 days of multiagent induction therapy beginning with the first dose of vinCRIStine
Patient may have started imatinib prior to study entry but has not received more than 14 days of imatinib
Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
Direct bilirubin =< 2.0 mg/dL
Shortening fraction of >= 27% by echocardiogram
Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
Corrected QT interval, QTc < 480 msec
Note: Repeat echocardiogram is not required if echocardiogram was obtained within 21 days of study enrollment
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2
Serum creatinine within normal limits based on age/gender, as follows
to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
>= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)

Exclusion Criteria

Known history of chronic myelogenous leukemia (CML)
ALL developing after a previous cancer treated with cytotoxic chemotherapy
Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
Down syndrome
Pregnancy and breast feeding
Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential
Lactating females who plan to breastfeed their infants
Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block
Prior treatment with dasatinib, or any BCR-ABL1 inhibitor other than imatinib
All patients and/or their parents or legal guardians must sign a written informed consent
All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
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