A Phase III Randomized Trial Investigating Bortezomib (NSC# 681239) on a Modified Augmented BFM (ABFM) Backbone in Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LLy)
Trial Snapshot
- Phase
- Phase 3
- Status
- Active, not recruiting
- Enrollment
- 847
- Locations
- 408
- Primary Endpoint
- Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients
Study Overview
Brief Summary
This randomized phase III trial compares how well combination chemotherapy works when given with or without bortezomib in treating patients with newly diagnosed T-cell acute lymphoblastic leukemia or stage II-IV T-cell lymphoblastic lymphoma. Bortezomib may help reduce the number of leukemia or lymphoma cells by blocking some of the enzymes needed for cell growth. It may also help chemotherapy work better by making cancer cells more sensitive to the drugs. It is not yet known if giving standard chemotherapy with or without bortezomib is more effective in treating newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.
Detailed Description
PRIMARY OBJECTIVES:
I. To compare event-free survival (EFS) in patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LLy) who are randomized to a modified augmented Berlin-Frankfurt-Munster (ABFM) backbone versus bortezomib plus the modified ABFM backbone.
SECONDARY OBJECTIVES:
I. To determine the safety and feasibility of modifying standard therapy for T-ALL and T-LLy based on the results of UKALL 2003, which includes a dexamethasone-based induction, additional doses of pegaspargase (PEG-ASP) during induction and delayed intensification (DI), and dexamethasone pulses during maintenance therapy.
II. To determine if prophylactic (presymptomatic) cranial radiation therapy (CRT) can be safely and effectively eliminated in the 85-90% of T-ALL patients classified as standard or intermediate risk.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 1 Year to 30 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •T-ALL: T-ALL patients must be enrolled on AALL08B1 or Project:EveryChild (APEC14B1, if open for the classification of ALL patients) prior to treatment and enrollment on AALL1231
- •All patients must be > 1 and < 31 years of age
- •Patients must have newly diagnosed T-lymphoblastic leukemia (T-ALL) or T-lymphoblastic lymphoma (T-LLy) stages II-IV
- •Note: a diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (cluster of differentiation [CD]19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a, and are present either in peripheral blood or > 25% in the bone marrow; if surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including terminal deoxynucleotidyl transferase (TdT), CD34 or CD99 will be assessed for expression; cases with uncertain expression will receive additional review within the appropriate Children's Oncology Group (COG) reference laboratory
- •For T-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to T-ALL; for tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of T-LLy defined by the submitting institution will be accepted
- •All patients and/or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria
- •Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of T-ALL, T-L-Ly or for any cancer diagnosis prior to the initiation of protocol therapy on AALL1231, with the exception of:
- •Steroid pretreatment: prednisone or methylprednisolone for =< 120 hours (5 days) in the 7 days prior to initiating induction chemotherapy or for =< 336 hours (14 days) in the 28 days prior to initiating induction chemotherapy; prior exposure to ANY steroids that occurred > 28 days before the initiation of protocol therapy does not affect eligibility; the dose of prednisone or methylprednisolone does not affect eligibility
- •Intrathecal cytarabine (the CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment) system chemotherapy must begin with 72 hours of this IT therapy; or
- •Pretreatment with hydroxyurea; or
- •600 cGy of chest irradiation, if medically necessary
- •Pre-treatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone use during sedation to prevent or treat airway edema; inhalation steroids and topical steroids are not considered pretreatment
- •Pre-existing >= grade 2 sensory or motor peripheral neurotoxicity
- •Uncontrolled seizure disorder
- •Diagnosis of Down syndrome (Trisomy 21)
- •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
- •Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
- •Patient has hypersensitivity to bortezomib, boron, or mannitol
- •Serious medical or psychiatric illness likely to interfere with participation in this clinical study
- •Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and within 30 days of any dose of bortezomib
Arms & Interventions
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Cyclophosphamide (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Daunorubicin (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Doxorubicin (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Mercaptopurine (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Hydrocortisone Sodium Succinate (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Doxorubicin Hydrochloride (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Etoposide (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Ifosfamide (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Dexamethasone (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Radiation Therapy (Radiation)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Thioguanine (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Mercaptopurine (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Pegaspargase (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Bortezomib (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Daunorubicin Hydrochloride (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Cyclophosphamide (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Vincristine Sulfate (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Hydrocortisone Sodium Succinate (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Doxorubicin Hydrochloride (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Etoposide (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Dexamethasone (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Radiation Therapy (Radiation)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Vincristine Sulfate (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Cytarabine (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Daunorubicin Hydrochloride (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Doxorubicin (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Vincristine (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Daunorubicin (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Methotrexate (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Methotrexate (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Pegaspargase (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Thioguanine (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Leucovorin Calcium (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Ifosfamide (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Vincristine (Drug)
Arm B (combination chemotherapy, bortezomib)
Patients receive combination chemotherapy with bortezomib (4 doses at 1.3 mg/m^2 during Induction and 4 doses at 1.3 mg/m^2 during Delayed Intensification). See Detailed Description.
Intervention: Cytarabine (Drug)
Arm A (combination chemotherapy)
Patients receive combination chemotherapy without bortezomib. See Detailed Description.
Intervention: Leucovorin Calcium (Drug)
Outcomes
Primary Outcomes
Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients
Time Frame: 3 years
EFS is calculated as time from randomization at study entry to first event (induction failure, induction death, relapse, second malignancy, remission death) or date of last contact. Three-year EFS rates will be calculated for both groups.
Secondary Outcomes
- EFS for Very High Risk (VHR) T-ALL Patients Treated With High Risk (HR) Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Become Minimal Residual Disease (MRD) Negative and Those Who Remain MRD Positive at the End of HR Block 3(3 years)
- Toxicity Rates Associated With Modified Standard Therapy, Including Dexamethasone and Additional Pegaspargase(3 years from start of therapy by patient)
- EFS for Standard (SR) and Intermediate Risk (IR) T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no Cranial Radiation Therapy [CRT]) and Similar Patients on AALL0434 (Received CRT)(3 years)
- Cumulative Incidence Rates of Isolated Central Nervous System (CNS) Relapse for SR and IR T-ALL Patients on the Non-bortezomib Containing Arm on This Study (no CRT) and Similar Patients on AALL0434 (Receive CRT)(3 years)
- EFS for Very High Risk (VHR) T-LLy Patients Treated With HR Berlin-Frankfurt-Munster (BFM) Intensification Blocks Who Have Complete or Partial Remission and Those Who do Not Respond(3 years)