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

Study ID
STU 082017-074

Study Sites

  • Children’s Medical Center (Dallas, Plano, Southlake)

Contact
Anil Shalwani
2144567353
Anil.Shalwani@childrens.com

Principal Investigator
Tamra Slone, M.D.

Official Title

International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones

Brief Overview

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 OBJECTIVES:
I. To compare disease-free survival (DFS) of standard risk pediatric Philapdelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG)/Berlin-Frankfurt-Munster (BFM) 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 disease-free survival (DFS) 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 Ph+ ALL patients between the two randomized arms.
TERTIARY OBJECTIVES:
I. To describe the toxicities associated with post-HSCT administration of imatinib.
II. To evaluate the long-term toxicities in patients treated with chemotherapy plus imatinib (no transplant), and explore the differences between arms.
III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy.
IV. To determine the prognostic significance of MRD at end of Induction IA. V. To evaluate MRD during post-Induction IB therapy in standard risk (SR) patients and explore whether there are any differences between randomized arms in the proportion of patients with non-detectable MRD at each time point.
VI. To evaluate MRD in high risk (HR) patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome.
VII. To evaluate concordance of MRD assessments made by immunoglobulin heavy chain (IGH)-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.
VIII. To determine prognostic significance of IKZF1 gene aberrations and deletions.
IX. To determine frequency and prognostic significance of p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.
X. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and methotrexate) for 6 months during the maintenance phase in standard risk Ph+ ALL patients.
XI. To identify factors associated with poor adherence. XII. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).
XIII. To measure adherence to imatinib after allogeneic HSCT in high risk 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) 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 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 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 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 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 and mesna IV 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 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 on days 1-21, high dose cytarabine IV over 3 hours on days 1-3, 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 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 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 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 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 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 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 on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of courses 1, 2, and 3, and mercaptopurine PO on days 1-84. Courses 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 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 and 4, 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 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 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 on day 43 in the absence of disease progression or unexpected toxicity.
INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD 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 on days 2 and 22 in the absence of disease progression or unexpected toxicity.
MAINTENANCE: Patients receive imatinib mesylate PO QD on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for course 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 course 1 and 2). Courses 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 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.

Eligibility

Inclusion Criteria:
- Patients who have not previously enrolled on AALL08B1 or APEC14B1 (if open for classification of newly diagnosed ALL patients) prior to enrollment on AALL1631, a baseline diagnostic sample must be available to develop an MRD probe
- Newly diagnosed de novo ALL (B-ALL or T-ALL) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or reverse transcriptase (RT)-PCR
- For patients who DO NOT enter AALL1631 via AALL08B1 or APEC14B1 (if open for classification of newly diagnosed ALL patients), laboratory reports detailing evidence of BCR-ABL1 fusion must be submitted for rapid central review within 72 hours of study enrollment
- Patients with known chronic myelogenous leukemia (CML) who develop lymphoid blast crisis are not eligible
- 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 induction therapy
- Patient has not had prior treatment with imatinib, dasatinib, or any other BCR-ABL1 inhibitor
- Karnofsky/Lansky performance status >= 60; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
- 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:
- 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
- 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
- 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
- 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
- 13 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; 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
- 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