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

Status
Active
Cancer Type
Leukemia
Trial Phase
Phase III
Eligibility
1 - 21 Years, Male and Female
Study Type
Treatment
NCT ID
NCT03007147
Protocol IDs
AALL1631 (primary)
AALL1631
NCI-2016-01588
AALL1631
Study Sponsor
Children's Oncology Group

Summary

This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called “ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.

Objectives

PRIMARY OBJECTIVE:
I. To compare disease-free survival (DFS) of standard risk (SR) 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 compare disease free survival (DFS) of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.
II. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients.
III. To determine event-free survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.
IV. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms.
V. To evaluate event free survival (EFS) and overall survival (OS) of all eligible Ph+ALL patients enrolled on the study.
VI. To evaluate OS in SR Ph+ ALL patients.
VII. To evaluate OS in HR Ph+ ALL patients.
VIII. To evaluate EFS and OS of all eligible ABL-class fusion positive ALL patients enrolled on the study.

EXPLORATORY OBJECTIVES:
I. To describe the toxicities associated with post-HSCT administration of imatinib in HR Ph+ALL patients.
II. To evaluate the long-term toxicities in SR Ph+ ALL patients treated with chemotherapy plus imatinib (no transplant), overall and between randomized 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 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.
VI. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.
VII. To determine prognostic significance of IKZF1 gene aberrations and deletions in Ph+ ALL patients.
VIII. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL.
IX. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and methotrexate) during the maintenance phase in SR Ph+ ALL patients in COG Centers only.
X. To identify factors associated with poor adherence.
XI. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined).
XII. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence in COG Centers only.
XIII. To compare DFS of SR ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.

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 3-6, 10-13, 17-20, and 24-27, and methotrexate IT on days 10 and 24.

POST-INDUCTION THERAPY: Patients classified as 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 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 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 1-3, 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 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 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 38-41 and 45-48, and methotrexate IT on days 38 and 45in 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 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 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 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.

Eligibility

  1. Diagnostic samples will be collected and analyzed according to the procedures of the National front-line protocol * Patients should be enrolled on National ALL protocol prior to enrollment on EsPhALL2017/COGAALL1631. Regardless of initial front-line protocol baseline diagnostic samples must be available to develop an MRD probe
  2. BCR-ABL1 fusion (Ph+): newly diagnosed 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
  3. ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions identified according to National/Center procedures of each participating country. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA, LYN. Methods of detection include fluorescence in-situ hybridization (FISH, e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based ribonucleic acid (RNA)-sequencing * Regardless of initial front-line protocol, laboratory reports detailing evidence of BCR-ABL1 or ABL-class fusion must be available for the National Trial Unit
  4. Ph+ ALL patients must have previously started induction therapy, which includes vincristine, a corticosteroid, usually PEG-L-asparaginase, with or without anthracycline, and/or other standard cytotoxic chemotherapy
  5. Ph+ ALL patients have not received more than 14 days of multiagent induction therapy beginning with the first dose of vincristine
  6. Ph+ ALL patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib
  7. ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy
  8. ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vincristine dose
  9. Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2
  10. Direct bilirubin =< 2.0 mg/dL
  11. Shortening fraction of >= 27% by echocardiogram
  12. Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
  13. Corrected QT interval, QTc < 480 msec * Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment
  14. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or 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)

Treatment Sites in Georgia

Atrium Health Navicent


Oncology Research, Atrium Health Navicent
777 Hemlock Street, MSC 123
(PACC 800 1st St, Ste 250)
Macon, GA 31201
4786332152
www.Atriumhealth.org

Study Coordinator:
Oncology Research Nurse
4786332152

Doctors:

Sushmita Nair
Vishwas Sakhalkar
Kristi George, MD
Abigail Cruz, MD
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.
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