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

Brief Title

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

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 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.
    

Detailed 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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Disease free survival (DFS)

Secondary Outcome

 Imatinib mesylate administration after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients

Condition

Acute Lymphoblastic Leukemia

Intervention

Allogeneic Hematopoietic Stem Cell Transplantation

Study Arms / Comparison Groups

 Arm A (imatinib mesylate, EsPhALL chemotherapy)
Description:  See Detailed Description

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

700

Start Date

July 28, 2017

Completion Date

June 30, 2028

Primary Completion Date

June 30, 2028

Eligibility Criteria

        Inclusion Criteria:

          -  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:

               -  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 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
      

Gender

All

Ages

2 Years - 21 Years

Accepts Healthy Volunteers

No

Contacts

Lewis B Silverman, MD, , 

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT03007147

Organization ID

AALL1631

Secondary IDs

NCI-2016-01588

Responsible Party

Sponsor

Study Sponsor

Children's Oncology Group

Collaborators

 National Cancer Institute (NCI)

Study Sponsor

Lewis B Silverman, MD, Principal Investigator, Children's Oncology Group


Verification Date

July 2020