Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia
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| ClinicalTrials.gov Identifier: NCT02101853 |
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Recruitment Status :
Active, not recruiting
First Posted : April 2, 2014
Results First Posted : December 6, 2022
Last Update Posted : November 21, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
This randomized phase III trial studies how well blinatumomab works compared with standard combination chemotherapy in treating patients with B-cell acute lymphoblastic leukemia that has returned after a period of improvement (relapsed). Immunotherapy with blinatumomab may allow the body's immune system to attack and destroy some types of leukemia cells. It is not yet known whether blinatumomab is more effective than standard combination chemotherapy in treating relapsed B-cell acute lymphoblastic leukemia.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Recurrent B Acute Lymphoblastic Leukemia | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Asparaginase Biological: Blinatumomab Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Etoposide Drug: Leucovorin Calcium Drug: Mercaptopurine Drug: Methotrexate Drug: Mitoxantrone Drug: Mitoxantrone Hydrochloride Drug: Pegaspargase Other: Pharmacological Study Radiation: Radiation Therapy Drug: Therapeutic Hydrocortisone Drug: Thioguanine Drug: Vincristine Drug: Vincristine Sulfate | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 669 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL) |
| Actual Study Start Date : | December 17, 2014 |
| Actual Primary Completion Date : | June 30, 2021 |
| Estimated Study Completion Date : | September 22, 2024 |
Resource links provided by the National Library of Medicine
Drug Information
available for:
Blinatumomab
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Arm A (HR and IR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019.
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Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HSCT
Other Names:
Drug: Asparaginase Given IM or IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT and IV or SC
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Leucovorin Calcium Given IV or PO
Other Names:
Drug: Methotrexate Given IT, IV, and PO
Other Names:
Drug: Mitoxantrone Given IV
Other Names:
Drug: Mitoxantrone Hydrochloride Given IV
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Other: Pharmacological Study Correlative studies Drug: Therapeutic Hydrocortisone Given IT
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm B (HR and IR blinatumomab)
Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT.
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Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HSCT
Other Names:
Biological: Blinatumomab Given IV
Other Names:
Drug: Cytarabine Given IT and IV or SC
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Methotrexate Given IT, IV, and PO
Other Names:
Other: Pharmacological Study Correlative studies Drug: Therapeutic Hydrocortisone Given IT
Other Names:
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Active Comparator: Arm C (LR control)
Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, Continuation 1 over 8 weeks, Continuation 2 over 8 weeks, and then Maintenance.
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Drug: Asparaginase
Given IM or IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT and IV or SC
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Leucovorin Calcium Given IV or PO
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given IT, IV, and PO
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Other: Pharmacological Study Correlative studies Radiation: Radiation Therapy Undergo cranial radiation therapy
Other Names:
Drug: Therapeutic Hydrocortisone Given IT
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: Arm D (LR blinatumomab)
Patients receive Block 2 over 4 weeks, Blinatumomab Cycle 1 over 5 weeks, Continuation 1 over 8 weeks, Blinatumomab Cycle 2 over 5 weeks, Continuation 2 over 8 weeks, Blinatumomab Cycle 3 over 5 weeks, and then Maintenance.
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Biological: Blinatumomab
Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT and IV or SC
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Leucovorin Calcium Given IV or PO
Other Names:
Drug: Mercaptopurine Given PO
Other Names:
Drug: Methotrexate Given IT, IV, and PO
Other Names:
Drug: Pegaspargase Given IV
Other Names:
Other: Pharmacological Study Correlative studies Radiation: Radiation Therapy Undergo cranial radiation therapy
Other Names:
Drug: Therapeutic Hydrocortisone Given IT
Other Names:
Drug: Thioguanine Given PO
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Primary Outcome Measures :
- Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients [ Time Frame: Up to 2 years from date of randomization ]DFS rates of HR and IR relapse B-ALL patients who are randomized following Induction Block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR Randomization). DFS is calculated as the time from randomization to date of first event (treatment failure, relapse, second malignancy, remission death) or date of last contact. Two-year DFS estimates will be calculated from date of randomization for both Arm A and Arm B. Two-sided 95% confidence intervals will be calculated.
- Disease Free Survival (DFS) of Low Risk (LR) Relapse Patients [ Time Frame: Up to 3 years from date of randomization ]DFS rates of LR relapse B-ALL patients who are randomized following Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR Randomization). DFS is calculated as the time from randomization to date of first event (relapse, second malignancy, remission death) or date of last contact. Three-year DFS estimates will be calculated from date of randomization for both Arm C and Arm D. Two-sided 95% confidence intervals will be calculated.
Secondary Outcome Measures :
- Overall Survival (OS) of HR and IR Relapse Patients [ Time Frame: Up to 2 years from date of randomization ]OS rates of HR and IR relapse B-ALL patients who are randomized following Induction Block 1 chemotherapy to receive either two intensive chemotherapy blocks or two 5-week blocks of blinatumomab (HR/IR Randomization). OS is calculated as the time from randomization to date of death or date of last contact. Two-year OS estimates will be calculated from date of randomization for both Arm A and Arm B. Two-sided 95% confidence intervals will be calculated.
- Overall Survival (OS) of LR Relapse Patients [ Time Frame: Up to 3 years from date of randomization ]OS rates of LR relapse B-ALL patients who are randomized following Block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR Randomization). OS is calculated as the time from randomization to date of death or date of last contact. Three-year OS estimates will be calculated from date of randomization for both Arm C and Arm D. Two-sided 95% confidence intervals will be calculated.
Other Outcome Measures:
- Rates of Minimal Residual Disease (MRD) Positivity (> 0.01%) [ Time Frame: Up to 12 weeks ]The rates at the end of Block 2 and Block 3 will be calculated for the randomized arms for HR and IR relapse patients.
- Hematologic Complete Remission Rate (for Treatment Failure Patients Not Previously Receiving Blinatumomab) [ Time Frame: Up to 12 weeks ]The observed rate will be calculated among patients with treatment failure who did not previously receive blinatumomab.
- MRD Negativity (< 0.01%) Rate (for Treatment Failure Patients Not Previously Receiving Blinatumomab) [ Time Frame: Up to 12 weeks ]The observed rate will be calculated among patients with treatment failure who did not previously receive blinatumomab.
- Proportion of Patients That Proceed to Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab (for Treatment Failure Patients Not Previously Receiving Blinatumomab) [ Time Frame: Up to 12 weeks ]The observed rate will be calculated among patients with treatment failure who did not previously receive blinatumomab.
- Feasibility of Rapid Taper of Immune Suppression for Subset of HSCT Patients With MRD >= 0.01% Pre- and/or Post-HSCT With no Acute Graft Versus Host Disease (aGVHD) [ Time Frame: Up to 10 years ]The observed rate of grade III-IV aGVHD among this subset will be calculated with 95% confidence intervals and compared descriptively to target rate.
- Safety of Rapid Taper of Immune Suppression for Subset of HSCT Patients With MRD >= 0.01% Pre- and/or Post-HSCT With no aGVHD Defined as < 5% Rate of Treatment-related Mortality (TRM) [ Time Frame: Up to 10 years ]The observed rate of TRM among this subset will be calculated with 95% confidence intervals and compared descriptively to target rate.
- Blinatumomab Pharmacokinetics (PK) [ Time Frame: Days 2 and 14 of cycle 1 ]Blinatumomab PK will be evaluated by summarizing blinatumomab steady state concentrations and systemic clearance obtained from non-compartmental analysis. In addition, a population PK approach using a non-linear mixed effect model will also be used to assess blinatumomab PK. Exposure-response analyses will be performed to explore associations among blinatumomab exposure, relevant clinical covariates and clinical measures of safety and efficacy.
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| Ages Eligible for Study: | 1 Year to 31 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Patients >= 1 year and < 31 years of age at the time of relapse will be eligible
- First relapse of B-ALL, allowable sites of disease include isolated bone marrow, combined bone marrow and CNS and/or testicular, and isolated CNS and/or testicular; extramedullary sites are limited to the CNS and testicles
- No waiting period for patients who relapse while receiving standard maintenance therapy
- Patients who relapse on frontline therapy in phases other than maintenance must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
- Cytotoxic therapy: at least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy, or maintenance chemotherapy, or intrathecal chemotherapy (methotrexate strongly preferred) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status
- Biologic (anti-neoplastic) agent: at least 7 days since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur
- Stem cell transplant or rescue: patient has not had a prior stem cell transplant or rescue
- Patient has not had prior treatment with blinatumomab
- With the exception of intrathecal chemotherapy (methotrexate strongly preferred; cytarabine is permissible) administered at the time of the required diagnostic lumbar puncture to establish baseline CNS status, patient has not received prior relapse-directed therapy (i.e., this protocol is intended as the INITIAL treatment of first relapse)
- Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
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Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- 1 to < 2 years: =< 0.6 mg/dL
- 2 to < 6 years: =< 0.8 mg/dL
- 6 to < 10 years: =< 1 mg/dL
- 10 to < 13 years: =< 1.2 mg/dL
- 13 to < 16 years: =< 1.5 mg/dL (males) and =< 1.4 mg/dL (females)
- >= 16 years: =< 1.7 mg/dL (males) and =< 1.4 mg/dL (females)
- Direct bilirubin < 3.0 mg/dL
- Shortening fraction of >= 27% by echocardiogram, or
- Ejection fraction of >= 50% by radionuclide angiogram
- All patients and/or their parent or legal guardian 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
Exclusion Criteria:
- Patients with Philadelphia chromosome positive/breakpoint cluster region protein (BCR)-Abelson murine leukemia viral oncogene homolog 1 (ABL1)+ ALL are not eligible
- Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia are not eligible
- Patients with T-lymphoblastic leukemia (T-ALL)/lymphoblastic lymphoma (T-LL) are not eligible
- Patients with B-lymphoblastic lymphoma (B-LL) are not eligible
- Patients with known optic nerve and/or retinal involvement are not eligible; patients who are presenting with visual disturbances should have an ophthalmologic exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
- Patients known to have one of the following concomitant genetic syndromes: Down syndrome, Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome
- Patients with known human immunodeficiency virus (HIV) infection
- Patients with known allergy to mitoxantrone, cytarabine, or both etoposide and etoposide phosphate (Etopophos)
- Lactating females who plan to breastfeed
- 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
- 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 pre-existing significant central nervous system pathology that would preclude treatment with blinatumomab, including: history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement are not eligible; patients with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible; (patients with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits have resolved)
- Patients with uncontrolled seizure disorder are not eligible; (patients with seizure disorders that do not require antiepileptic drugs, or are well controlled with stable doses of antiepileptic drugs remain eligible)
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): NCT02101853
Locations
Show 186 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Patrick A Brown | Children's Oncology Group |
Study Documents (Full-Text)
Documents provided by National Cancer Institute (NCI):
Documents provided by National Cancer Institute (NCI):
Study Protocol and Statistical Analysis Plan [PDF] December 19, 2019
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT02101853 |
| Other Study ID Numbers: |
NCI-2014-00631 NCI-2014-00631 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) s15-00970 COG-AALL1331 AALL1331 ( Other Identifier: Children's Oncology Group ) AALL1331 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) U10CA098543 ( U.S. NIH Grant/Contract ) |
| First Posted: | April 2, 2014 Key Record Dates |
| Results First Posted: | December 6, 2022 |
| Last Update Posted: | November 21, 2023 |
| Last Verified: | September 2023 |
Additional relevant MeSH terms:
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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Calcium, Dietary Leucovorin Folic Acid Cytarabine Dexamethasone Dexamethasone acetate |
Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate Cyclophosphamide Methotrexate Etoposide Vincristine Etoposide phosphate Asparaginase Mitoxantrone Mercaptopurine Podophyllotoxin Pegaspargase Thioguanine |