Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia
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| ClinicalTrials.gov Identifier: NCT02003222 |
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Recruitment Status :
Active, not recruiting
First Posted : December 6, 2013
Last Update Posted : December 15, 2023
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Sponsor:
National Cancer Institute (NCI)
Collaborator:
Canadian Cancer Trials Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
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. Immunotherapy with monoclonal antibodies, such as blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating newly diagnosed acute lymphoblastic leukemia.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Lymphoblastic Leukemia B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Procedure: Biospecimen Collection Biological: Blinatumomab Procedure: Bone Marrow Aspiration Procedure: Bone Marrow Biopsy Drug: Cyclophosphamide Drug: Cytarabine Drug: Daunorubicin Drug: Daunorubicin Hydrochloride Drug: Dexamethasone Drug: Etoposide Procedure: Lumbar Puncture Drug: Mercaptopurine Drug: Methotrexate Drug: Pegaspargase Drug: Prednisone Biological: Rituximab Drug: Vincristine Drug: Vincristine Sulfate Procedure: X-Ray Imaging | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 488 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (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 |
| Actual Study Start Date : | May 19, 2014 |
| Actual Primary Completion Date : | June 23, 2023 |
| Estimated Study Completion Date : | December 4, 2024 |
Resource links provided by the National Library of Medicine
Drug Information
available for:
Blinatumomab
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (blinatumomab, chemotherapy)
See Detailed Description
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Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic SCT
Other Names:
Procedure: Biospecimen Collection Undergo blood sample collection
Other Names:
Biological: Blinatumomab Given IV
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Given IV
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone Given PO
Other Names:
Drug: Etoposide Given IV
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given PO, IT or IV
Other Names:
Drug: Pegaspargase Given IM or IV
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
Procedure: X-Ray Imaging Undergo x-ray imaging
Other Names:
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Active Comparator: Arm II (chemotherapy)
See Detailed Description
|
Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic hematopoietic SCT
Other Names:
Procedure: Biospecimen Collection Undergo blood sample collection
Other Names:
Procedure: Bone Marrow Aspiration Undergo bone marrow aspiration Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT, IV, or SC
Other Names:
Drug: Daunorubicin Given IV
Other Names:
Drug: Daunorubicin Hydrochloride Given IV
Other Names:
Drug: Dexamethasone Given PO
Other Names:
Drug: Etoposide Given IV
Other Names:
Procedure: Lumbar Puncture Undergo lumbar puncture
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given PO, IT or IV
Other Names:
Drug: Pegaspargase Given IM or IV
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
Procedure: X-Ray Imaging Undergo x-ray imaging
Other Names:
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Primary Outcome Measures :
- Overall survival [ Time Frame: Time between randomization and death from any cause, assessed up to 10 years ]Medians and confidence intervals will be calculated using the Kaplan-Meier method. Comparison of overall survival between treatment arms will be conducted using the one-sided stratified log-rank test with minimal residual disease status, age, CD20 status, rituximab use, and whether patients intend to receive hematopoietic stem cell transplantation or not as stratification factors. 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 :
- Relapse-free survival [ Time Frame: Time from randomization to relapse or death without documentation of relapse, assessed up to 10 years ]Estimates of relapse-free survival, including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Comparison of relapse-free survival between treatment arms will be conducted using the one-sided stratified log-rank test with minimal residual disease status, age, CD20 status, rituximab use, and whether patients intend to receive hematopoietic stem cell transplantation or not as stratification factors. Stratified on those factors, Cox proportional hazards models, will also be used to assess the treatment effect by adjusting other possible clinical and biological risk factors, including cytogenetic abnormalities and the receipt of transplant (included as a time-varying covariate).
- Minimal residual disease (MRD) status [ Time Frame: Up to 32 weeks ]Patients who are MRD positive at step 3 randomization/ registration and then convert to MRD negative (-) after 2 cycles of blinatumomab will be compared to those patients who are MRD- at randomization and remain MRD- after 2 cycles of blinatumomab or consolidation chemotherapy. The study will have 80% power to detect 56% reduction in hazard rate in the MRD- remain as MRD- patients (after blinatumomab/consolidation chemotherapy), using one-sided log rank test at the significance level of 0.025 and assuming 2 years of follow-up
- Incidence of adverse events [ Time Frame: Up to 10 years ]Will be assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. 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 ]Cox regression analysis will be used to assess whether BCR-ABL-like phenotype is an independent predictor for overall survival (and relapse-free survival), adjusted by treatment effect, minimal residual disease status, age, cytogenetic abnormalities, CD20 status, rituximab use, and whether patients intend to receive hematopoietic stem cell transplantation 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.
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| Ages Eligible for Study: | 30 Years to 70 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Criteria
Inclusion Criteria:
- PRE-REGISTRATION
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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 Research Laboratory (LTRL) and reported to the institution
- NOTE: IT IS ESSENTIAL THAT A SAMPLE CONTAINING SUFFICIENT BLAST CELLS BE SUBMITTED TO THE ECOG-ACRIN LTRL AT BASELINE SO THAT SUBSEQUENT BONE MARROW ASSESSMENTS OF MRD CAN BE DONE; IN ADDITION TO ALLOWING THE LTRL TO CONFIRM ELIGIBILITY BASED ON BLAST CELL IMMUNOPHENOTYPE AND BCR/ABL STATUS, IT IS ALSO IMPERATIVE THAT AN ADEQUATE NUMBER OF BLASTS BE BANKED FOR ANALYSIS BY DRS MULLIGHAN/WILLMAN. WITHOUT ADEQUATE BASELINE SAMPLES, PATIENTS WILL NOT BE ABLE TO BE TREATED AND RANDOMIZED ON THIS PROTOCOL; IF A BONE MARROW ASPIRATE IS NOT AVAILABLE FOR LTRL SUBMISSION AT BASELINE, IT IS IMPERATIVE THAT DR PAIETTA FROM THE LTRL IS CALLED TO DISCUSS THE PERIPHERAL BLOOD WBC AND BLAST COUNT BEFORE BLOOD ONLY IS SUBMITTED
- NOTE: Hydroxyurea can be given for up to 5 days prior to initiation of protocol therapy for control of leukocyte count and/or other symptoms or signs; corticosteroids can be given after pre-registration to the protocol and submission of baseline marrow and blood samples for control of leukocyte count and/or other symptoms or signs prior to initiation of protocol therapy if needed; if corticosteroids are given prior to pre-registration, contact the study chair as the patient may still be eligible to participate
- INDUCTION ELIGIBILITY CRITERIA-STEP 1
- Age >= 30 years and =< 70 years
- 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
- 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); if there are few or no circulating blasts and an adequate marrow sample cannot be obtained for cytogenetic analysis, the patient may still enroll on the trial
- Serum direct bilirubin < 2 mg/dl or serum total bilirubin =< 3 (obtained =< 48 hours prior to registration); NOTE: the above stipulation for normal hepatic function does not apply if liver dysfunction is due to leukemia infiltration
- Serum creatinine < 2 mg/dl (obtained =< 48 hours prior to registration); 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
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Patients with known human immunodeficiency virus (HIV) infection are eligible if they meet all of the following criteria:
- No history of acquired immune deficiency syndrome (AIDS)-related complications other than a history of low CD4+ T-cell count (< 200/mm^3) prior to initiation of combination antiretroviral therapy; on study CD4+ T-cell count may not be informative due to leukemia and should not be used as an exclusion criterion if low
- Patient must be healthy on the basis of HIV disease with high likelihood of near normal life span were it not for the leukemia
- Patient must have serum HIV viral load of < 200 copies/mm^3
- Patient must be on combination antiretroviral therapy with minimal pharmacokinetic interactions with study therapy and minimal overlapping clinical toxicity with protocol therapy
- Patient must not be receiving protease inhibitors or once daily formulations containing cobicistat, stavudine, or on regimens containing stavudine or zidovudine
- It is recommended to utilize a regimen of the integrase inhibitor, dolutegravir, combined with either disoproxil fumarate/emtricitabine or dolutegravir combined with tenofovir alafenamide/emtricitabine
- Patient must have no history of recent myocardial infarction (within three months), uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia
- 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
- Women must not be pregnant or breast-feeding due to administration of teratogenic chemotherapy 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 (obtained =< 48 hours prior to registration)
- Serum direct bilirubin < 2 mg/dL or serum total bilirubin =< 3 (obtained =< 48 hours prior to registration)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN) (obtained =< 48 hours prior to registration)
- RANDOMIZATION OR ASSIGNMENT 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
- Patients must have resolved any serious infectious complications related to therapy
- Any significant medical complications related to therapy must have resolved
- Direct or total 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 Research Laboratory
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MRD results will be reported to the submitting institution
- 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
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In B-lineage ALL, MRD levels in peripheral blood or from a dilute marrow aspiration can be 300% lower, on average, than those in bone marrow at a given time point; submitting a first pull from a separate aspiration site will ensure that MRD determinations used in randomization and trial interpretation are accurate
- 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 OR ASSIGNMENT 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
- 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
Exclusion Criteria:
- Mature B ALL (Burkitt's-like leukemia) is excluded from enrollment in this trial; pre-study bone marrow biopsy and aspirate must be completed =< 1 week prior to registration
- Patient must not have a concurrent active malignancy for which they are receiving treatment
- Patient must not have intercurrent organ damage or medical problems that will jeopardize the outcome of therapy (i.e., psychiatric disorder, drug abuse, pregnancy)
- Patient must not have an antecedent hematologic disorder
- 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 not have an active uncontrolled infection
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02003222
Locations
Show 551 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Canadian Cancer Trials Group
Investigators
| Principal Investigator: | Mark R Litzow | ECOG-ACRIN Cancer Research Group |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT02003222 |
| Other Study ID Numbers: |
NCI-2013-02229 NCI-2013-02229 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) ECOG-E1910 E1910 PE1910_A08PAMDREVW01 E1910 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) E1910 ( Other Identifier: CTEP ) U10CA021115 ( U.S. NIH Grant/Contract ) U10CA180820 ( U.S. NIH Grant/Contract ) U24CA196172 ( U.S. NIH Grant/Contract ) |
| First Posted: | December 6, 2013 Key Record Dates |
| Last Update Posted: | December 15, 2023 |
| Last Verified: | December 2023 |
Additional relevant MeSH terms:
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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Philadelphia Chromosome Neoplasms by Histologic Type Neoplasms Hematologic Diseases Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Translocation, Genetic Chromosome Aberrations Pathologic Processes Cytarabine |
Dexamethasone Dexamethasone acetate Prednisone Cortisone Cyclophosphamide Rituximab Methotrexate Etoposide Vincristine Etoposide phosphate Daunorubicin Asparaginase Mercaptopurine Podophyllotoxin Pegaspargase |