Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02003222
First received: December 2, 2013
Last updated: October 23, 2014
Last verified: October 2014
  Purpose

This randomized phase III trial studies combination chemotherapy with blinatumomab to see how well it works compared to induction chemotherapy alone in treating patients with newly diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL)-negative B lineage acute lymphoblastic leukemia. 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. Monoclonal antibodies, such as blinatumomab, may block cancer growth in different ways by targeting certain cells. It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating newly diagnosed acute lymphoblastic leukemia.


Condition Intervention Phase
B-cell Adult Acute Lymphoblastic Leukemia
Untreated Adult Acute Lymphoblastic Leukemia
Drug: cytarabine
Drug: daunorubicin hydrochloride
Drug: vincristine sulfate
Drug: dexamethasone
Drug: methotrexate
Drug: pegaspargase
Drug: cyclophosphamide
Drug: mercaptopurine
Biological: blinatumomab
Drug: etoposide
Drug: prednisone
Procedure: allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized Trial of Blinatumomab for Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia in Adults

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • OS [ Time Frame: Time between randomization and death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
    Medians and confidence intervals will be calculated using the Kaplan-Meier method. Comparison of OS between treatment arms will be conducted using the one-sided stratified log-rank test. A Cox proportional hazards model will be used to assess the effect of treatment and will include receipt of transplant as a time-varying covariate.


Secondary Outcome Measures:
  • MRD status [ Time Frame: Up to 32 weeks ] [ Designated as safety issue: No ]
    MRD will be assessed after induction and intensification chemotherapy (but before randomization), after two courses of blinatumomab or consolidation, and prior to the start of the maintenance therapy. The study will have 91% power to detect this difference using two-sided Fisher's exact test at the significance level of 0.05.

  • Incidence of adverse events, per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    Classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated or unlikely to be related" to study treatment in the event of an actual relationship developing.


Other Outcome Measures:
  • Identification and characterization of the BCR/ABL1-like phenotype [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Cox regression analysis will be used to assess whether BCR-ABL-like phenotype is an independent predictor for OS, adjusted by treatment effect, MRD status, age, cytogenetic abnormalities, WBC counts, and whether patients intend to receive HSCT or not. If a strong interaction effect is detected, Cox regression analysis will be used to look at the treatment difference separately within each of the BCR-ABL-like phenotype categories (negative/positive) to see if the magnitude and direction of the treatment effect differs by phenotype.


Estimated Enrollment: 360
Study Start Date: December 2013
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (blinatumomab, chemotherapy)
See Detailed Description
Drug: cytarabine
Given IT or IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Drug: methotrexate
Given PO, IT or IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
Drug: pegaspargase
Given IM or IV
Other Names:
  • L-asparaginase with polyethylene glycol
  • Oncaspar
  • PEG-ASP
  • PEG-L-asparaginase
Drug: cyclophosphamide
Given PO or IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: mercaptopurine
Given PO
Other Names:
  • 6-mercaptopurine
  • 6-MP
  • Leukerin
  • MP
Biological: blinatumomab
Given IV
Other Names:
  • anti-CD19/anti-CD3 recombinant bispecific monoclonal antibody MT103
  • bispecific T-cell engager MT103
  • MEDI-538
  • MT-103
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: prednisone
Given PO
Other Names:
  • DeCortin
  • Deltra
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic SCT
Other: laboratory biomarker analysis
Correlative studies
Active Comparator: Arm II (chemotherapy)
See Detailed Description
Drug: cytarabine
Given IT or IV
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Cerubidin
  • Cerubidine
  • daunomycin hydrochloride
  • daunorubicin
  • RP-13057
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: dexamethasone
Given PO
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM
Drug: methotrexate
Given PO, IT or IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
Drug: pegaspargase
Given IM or IV
Other Names:
  • L-asparaginase with polyethylene glycol
  • Oncaspar
  • PEG-ASP
  • PEG-L-asparaginase
Drug: cyclophosphamide
Given PO or IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: mercaptopurine
Given PO
Other Names:
  • 6-mercaptopurine
  • 6-MP
  • Leukerin
  • MP
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Drug: prednisone
Given PO
Other Names:
  • DeCortin
  • Deltra
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic SCT
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02003222

  Show 217 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Mark Litzow ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02003222     History of Changes
Other Study ID Numbers: NCI-2013-02229, NCI-2013-02229, ECOG-E1910, E1910, E1910, U10CA021115, U10CA180820
Study First Received: December 2, 2013
Last Updated: October 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
6-Mercaptopurine
Antibodies, Bispecific
Asparaginase
Cyclophosphamide
Cytarabine
Daunorubicin
Dexamethasone
Methotrexate
Pegaspargase
Vincristine
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Alkylating Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antibiotics, Antineoplastic
Antiemetics
Antimetabolites
Antimetabolites, Antineoplastic
Antimitotic Agents
Antineoplastic Agents

ClinicalTrials.gov processed this record on October 23, 2014