A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia in Adults

Location:

Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

PRIMARY OBJECTIVES: I. To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with BCR-ABL-negative B cell precursor acute lymphoblastic leukemia (ALL) who are minimal residual disease (MRD) positive after induction and intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of residual blasts. II. If superiority of blinatumomab in the MRD positive group is shown, to compare the OS of blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with BCR-ABL-negative B cell precursor ALL who are MRD negative after induction and intensification chemotherapy, based on MFC assessment of residual blasts. III. If superiority of blinatumomab in the MRD positive group is not shown, to compare the OS of blinatumomab in conjunction with chemotherapy to chemotherapy alone in the overall population of patients with BCR-ABL-negative B cell precursor ALL. SECONDARY OBJECTIVES: I. To determine if blinatumomab can convert patients who are MRD positive by MFC assessment of residual blasts after induction and intensification chemotherapy to MRD negativity. II. To assess the toxicities of blinatumomab in this patient population. III. To assess the toxicities of the modified E2993 chemotherapy regimen in this patient population. IV. To describe the outcome of patients who proceed to allogeneic blood or marrow transplant after treatment with or without blinatumomab. TERTIARY OBJECTIVES: I. To determine differences in MRD kinetics among patients with the BCR/ABL1-like B-lineage ALL, and assess the efficacy of blinatumomab in each molecular subgroup. II. To evaluate the incidence of anti-blinatumomab antibody formation. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive cytarabine intrathecally (IT) on day 1; daunorubicin hydrochloride intravenously (IV) over 10-15 minutes on day 1, 8, 15, and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on days 1-7 (and 15-21 for patients age < 55 years only); methotrexate IT on day 14; and pegaspargase intramuscularly (IM) or IV on day 18 (patients age =< 55 years). Beginning on day 29, patients with absolute neutrophil count (ANC) >= 0.75 x 10^9/L and platelets > 75 x 10^9/L (patients with delayed hematologic recovery) receive cyclophosphamide IV over 30 minutes on days 1 and 29, cytarabine IV over 30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine tablet PO on days 1-14, 29-42, pegaspargase IM or IV on day 15 (patients age < 55 years), and methotrexate IT or IV over 6 hours on days 1, 8, 15, and 22. INTENSIFICATION THERAPY: Beginning 4 weeks after the completion of course 2 of induction therapy, patients achieving complete response (CR) or complete response with incomplete recovery (CRi) receive intensification therapy comprising high-dose methotrexate IV over 2 hours on days 1 and 8, and pegaspargase IM or IV on day 9. Patients are then randomized to 1 of 2 treatment arms. Patients randomized to the blinatumomab group receive blinatumomab IV continuously on days 1-28. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients may then undergo allogeneic stem cell transplant (SCT) or proceed to consolidation therapy per investigator discretion. CONSOLIDATION THERAPY: Beginning after the second course of blinatumomab (patients randomized to the blinatumomab group) or after intensification therapy (patients not randomized to blinatumomab), patients receive cytarabine IV over 30 minutes on days 1-5, etoposide IV over 1 hour on days 1-5, methotrexate IT on day 1, and pegaspargase IM or IV on day 5. Beginning 4 weeks from day 1 of course 1, patients receive cytarabine, etoposide, and methotrexate as in course 1. Beginning 4 weeks from day 1 of course 2, patients receive daunorubicin hydrochloride IV over 10-15 minutes on day 1, 8, 15, and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone PO daily on days 1-7 (and 15-21 for patients age < 55 years); methotrexate IT or IV over 6 hours on day 1; cyclophosphamide PO or IV over 30 minutes on day 29; cytarabine IV over 30 minutes on days 31-34 and 38-41; and mercaptopurine tablet PO on days 29-42. Beginning 8 weeks from day 1 of course 3, patients receive cytarabine, etoposide, and methotrexate as in course 1. Patients randomized to blinatumomab repeat course 4 and then receive blinatumomab IV continuously on days 1-28. MAINTENANCE THERAPY: Within 12 weeks after beginning last course of consolidation therapy, patients receive mercaptopurine tablet PO daily, methotrexate PO or IV over 6 hours once weekly for 2.5 years, vincristine sulfate IV once every 3 months, prednisone PO on days 1-5 every 3 months. Treatment continues for up to 2.5 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Who is eligible to participate?

Inclusion Criteria: - PRE-REGISTRATION - Diagnostic bone marrow and peripheral blood specimens must be submitted for immunophenotyping and selected molecular testing, and the establishment of BCR/ABL status; testing will be performed by the Eastern Cooperative Oncology Group (ECOG)-American College of Radiation Imaging Network (ACRIN) Leukemia Translational Studies Laboratory and reported to the institution - NOTE: IT IS ESSENTIAL THAT A BONE MARROW ASPIRATE IS OBTAINED FROM THE BASELINE BONE MARROW ASPIRATE/BIOPSY FOR CENTRAL IMMUNOPHENOTYPING SO THAT SUBSEQUENT BONE MARROW ASSESSMENTS OF MRD CAN BE DONE; WITHOUT THESE SAMPLES PATIENTS WILL NOT BE ABLE TO BE TREATED AND RANDOMIZED ON THIS PROTOCOL - INDUCTION ELIGIBILITY CRITERIA-STEP 1 - New diagnosis of B lineage ALL must be made upon bone marrow or peripheral blood immunophenotyping; cases with myeloid antigen expression, but unequivocal lymphoid immunophenotype, are eligible - Mature B ALL (Burkitt's-like leukemia) is excluded from enrollment in this trial - Negativity for the Philadelphia chromosome must be established by conventional cytogenetics, fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR); patients who are negative for the Philadelphia chromosome by conventional cytogenetics must have FISH or PCR performed for BCR/ABL to exclude occult translocations - Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if adequate number of circulating blasts from peripheral blood; FISH testing for common B-lineage ALL abnormalities including t(9;22) (BCR/ABL1), t(12;21) (ETS-variant gene 6 [ETV6]/Runt-related transcription factor 1 [RUNX1]), t(1;19) (pre-B-cell leukemia homeobox 1 [PBX1]/transcription factor 3 [TCF3]), +4,+10,+17, (centromeric [Cen]4/Cen10/Cen17), t(11q23;var), (myeloid/lymphoid or mixed lineage leukemia [MLL]), deletion (del)(9p) (cyclin-dependent kinase inhibitor 2A [CDKN2A]/Cen9), and t(14;var) (immunoglobulin heavy chain [IGH] is encouraged) - Patient must not have a concurrent active malignancy for which they are receiving treatment - Serum direct bilirubin < 2 mg/dl; NOTE: The above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration - Serum creatinine < 2 mg/dl; NOTE: The above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration - Patient should be human leukocyte antigen (HLA) typed (A, B, C, DR and DQ) during induction therapy phase or a written explanation for not undergoing HLA typing on the flow sheet - Patient must not have intercurrent organ damage or medical problems that will jeopardize the outcome of therapy (i.e., psychiatric disorder, drug abuse, pregnancy) - Human immunodeficiency virus (HIV) infected persons are not eligible - Patient must not have an antecedent hematologic disorder - Patient must have no history of recent myocardial infarction (within three months), uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia - Patient must not have a history or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia; Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis, or other significant CNS abnormalities - Patient must have a normal cardiac ejection fraction by pretreatment multigated acquisition scan (MUGA) or echocardiogram within 4 weeks prior to registration (resting ejection fraction >= 40% or >= 5% increase with exercise), shortening fraction by echocardiogram >= 24%, or to within the normal range of values for the institution - Patient must not have an active uncontrolled infection - Women must not be pregnant or breast-feeding and must not become pregnant or breastfeed during protocol therapy and for at least 3 months after protocol therapy; woman of childbearing potential must abstain from sexual activity or be willing to use 2 highly effective forms of contraception throughout protocol therapy and for at least an additional 3 months after the last dose of protocol-specified therapy; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Men who have a female partner of childbearing potential must be willing to use 2 highly effective forms of contraception throughout protocol therapy and for at least an additional 3 months after the last dose of protocol-specified therapy; men who have a pregnant partner must be willing to use a condom during sexual activity throughout protocol therapy and for 3 months after the last dose of protocol-specified therapy - ECOG performance score 0-3 - Patient must have given written informed consent - POST-INDUCTION THERAPY ELIGIBILITY CRITERIA (PRIOR TO INTENSIFICATION-STEP 2) - ECOG performance status 0-2 - Patients must have achieved a CR or CRi - Patients who have achieved a CR or CRi must have maintained peripheral blood evidence of a CR or CRi - Patient must be CNS (cerebrospinal fluid [CSF]) negative for leukemia - Patients must have resolved any serious infectious complications related to induction - Any significant medical complications related to induction must have resolved - Serum creatinine =< 2.0 mg/dl - Serum direct bilirubin < 2 mg/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) - RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3 - Patients must have an ECOG performance status of 0-2 - Patients must have maintained peripheral blood evidence of a remission and must have a CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy and cytogenetic analysis - Patients must have resolved any serious infectious complications related to therapy - Any significant medical complications related to therapy must have resolved - Direct bilirubin < 1.5 x ULN (unless related to Gilbert's or Meulengracht's syndrome); the values must be obtained within 48 hours prior to randomization - Serum creatinine < 1.5 x ULN; the values must be obtained within 48 hours prior to randomization - Bone marrow aspirates must be submitted for centralized minimal residual disease (MRD) assessment performed by the ECOG-ACRIN Leukemia Translational Studies Laboratory; NOTE: FOR MRD ASSESSMENTS, AN ASPIRATE FROM A SEPARATE BONE MARROW ASPIRATION SITE MUST BE SUBMITTED; (THE NEEDLE CAN BE RE-DIRECTED THROUGH THE SAME SKIN PUNCTURE SITE); ONLY SUBMIT ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION SITE FOR MRD TESTING; DO NOT SUBMIT SAMPLES FROM THE SECOND OR THIRD PULL OF THE SAME ASPIRATION SITE - NOTE: failure to submit bone marrow aspirates will result in a major violation at the time of an audit - CRITERIA FOR ALLOGENEIC TRANSPLANTATION - A suitable donor must be identified; there are no restrictions on donor type and can include a matched sibling, a matched or mismatched unrelated donor, a family haplotype matched donor or a cord blood donor (single or double) - Patients should meet the eligibility criteria for RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3 - Patients must be considered reliable enough to comply with the medication regimen and follow-up, and have social support necessary to allow this compliance - CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have an ECOG performance status of 0-3 - CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have maintained peripheral blood evidence of a remission and must have a CR or CRi, confirmed on restaging BM aspirate and biopsy and cytogenetic analysis - CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have resolved any serious infectious complications related to therapy - CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Any significant medical complications related to therapy must have resolved

Last updated:

9/16/2014

NCT ID:

NCT02003222

IRB Number:

14-000209