Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare disease free survival (DFS) of high-risk (HR) and intermediate-risk (IR) relapse B-cell acute lymphoblastic leukemia (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) as a part of a treatment regimen prior to allogeneic bone marrow transplantation. (Closed to enrollment effective September 18, 2019) II. To compare the DFS of low risk (LR) relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization). (Closed to enrollment effective September 30, 2019) SECONDARY OBJECTIVES: I. To compare overall survival (OS) 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). (Closed to enrollment effective September 18, 2019) II. To compare OS of LR relapse B-ALL patients who are randomized following block 1 chemotherapy to receive either chemotherapy alone or chemotherapy plus blinatumomab (LR randomization). EXPLORATORY OBJECTIVES: I. To compare the rates of minimal residual disease (MRD) >= 0.01% at the end of block 2 and block 3 for HR and IR relapse B-ALL patients in HR/IR randomization. II. To estimate, for treatment failure (TF) patients not previously receiving blinatumomab, the hematologic complete remission rate (CR), rate of MRD < 0.01%, and proportion able to proceed to hematopoietic stem cell transplant (HSCT) in CR after treatment with blinatumomab. III. To assess the feasibility and safety of rapid taper of immune suppression for the subset of HSCT patients with MRD >= 0.01% pre- and/or post-HSCT with no acute graft versus host disease (aGVHD). IV. To evaluate blinatumomab pharmacokinetics (PK) and explore exposure-response relationships for measures of safety and effectiveness. OUTLINE: All patients receive Block 1 over 4 weeks. BLOCK 1: Patients receive dexamethasone orally (PO) twice daily (BID) or intravenously (IV) on days 1-5 and 15-19; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 3 and 17; mitoxantrone hydrochloride IV over 15-30 minutes on days 1-2, and methotrexate intrathecally (IT) on day 1. Patients with central nervous system (CNS) 1 or CNS2 also receive methotrexate IT on day 8. Patients with CNS3 (including isolated CNS relapse) also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8, 15, and 22. High risk and intermediate risk patients are then assigned to randomization R1. Low risk patients are assigned to randomization R2. RANDOMIZATION R1 (HR and IR patients): Patients are randomized to 1 of 2 treatment arms. Effective 09/18/2019, HR/IR patients not yet randomized are not eligible for post-Induction therapy on AALL1331 and will be removed from protocol therapy. Patients receiving therapy on Arm A prior to Amendment #10A who have not yet received day 22 treatment on Block 3 will be offered the opportunity to cross over to Arm B to receive blinatumomab. ARM A: Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT if eligible. Patients with persistent testicular involvement after Block 1 receive testicular radiation during the Block 2. ARM B: Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT if eligible. Patients with persistent testicular involvement after Block 1 receive testicular radiation during the first block of blinatumomab. RANDOMIZATION R2 (LR patients): LR patients are randomized to 1 of 2 treatment arms. ARM C: 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. CNS3 patients receive chemoradiation post-Maintenance Cycle 1. Patients with persistent testicular involvement after Block 1 receive testicular radiation during Block 2. ARM D: 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. CNS3 patients receive chemoradiation post Maintenance Cycle 1. Patients with persistent testicular involvement after Block 1 receive testicular radiation during Block 2. BLOCK 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; methotrexate IV over 36 hours on day 8; leucovorin calcium IV or PO on days 10-11; pegaspargase IV over 1-2 hours on day 9 or 10; cyclophosphamide IV over 15-30 minutes on days 15-19; and etoposide IV over 1-2 hours on days 15-19. Patients with CNS1 or CNS2 also receive methotrexate IT on day 8. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 22. BLOCK 3: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; cytarabine IV over 3 hours every 12 hours on days 1, 2, 8, and 9; asparaginase intramuscularly (IM) or IV over 1 hour on days 2, 4, 9, 11, and 23; methotrexate IT on day 1and IV over 36 hours on day 22; leucovorin calcium PO or IV on days 24-25. Patients with CNS1 or CNS2 also receive methotrexate IT on day 22. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 22. BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 15 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 15 and 29. BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV continuously on days 1-28. Patients with CNS1 or CNS2 also receive methotrexate IT on days 8 and 29. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 8 and 29. BLINATUMOMAB BLOCK 3: Patients receive blinatumomab IV continuously on days 1-28 and dexamethasone PO or IV on day 1. CONTINUATION 1 & 2: Patients receive dexamethasone PO BID or IV on days 1-5; vincristine sulfate IV over 1 minute on day 1; mercaptopurine tablet PO on days 1-42; methotrexate PO on days 8, 15, 29, and 36; or; cyclophosphamide IV over 15-30 minutes on days 43 and 50; etoposide IV over 1-2 hours on days 43 and 50; thioguanine PO once daily on days 43-49; and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 44-47 and 51-54. Patients with CNS1 or CNS2 also receive methotrexate IT on days 1 and 43, methotrexate PO every 6 hours for 4 doses on day 22, leucovorin calcium PO every 6 hours for 2 doses on day 24. Patients with CNS3 also receive methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1 and 43 ; methotrexate IV over 36 hours on day 22; and leucovorin calcium IV or PO every 6 hours on days 24-25. MAINTENANCE: Patients receive dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; vincristine sulfate IV over 1 minute on days 1, 29, and 57; mercaptopurine tablet PO on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Patients with CNS1 or CNS2 also receive methotrexate IT on day 1. Patients with CNS3 receive Triple Intrathecal Therapy (ITT) on day 1. Cycles repeat every 12 weeks for up to 2 years from the beginning of treatment in the absence of disease progression or unacceptable toxicity. MAINTENANCE CHEMORADIATION (LR CNS3 PATIENTS ONLY): Following maintenance cycle 1, patients receive 1800 cGy cranial radiation; dexamethasone PO BID or IV on days 1-7 and 15-21; vincristine sulfate IV over 1 minute on days 1, 8 and 15; and pegaspargase IV over 1-2 hours on day 1. Patients then resume maintenance with cycle 2 and beyond. After completion of study treatment, patients are followed up annually for 10 years.

Official Title
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Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC#765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL)

Conditions
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Recurrent B Acute Lymphoblastic Leukemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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 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)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 31 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (HR and IR control)<br>Patients receive Block 2 over 4 weeks, Block 3 over 4 weeks, and then undergo allogeneic HSCT. Closed effective September 18, 2019. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Asparaginase<br>* Given IM or IV<br>* Other names: Spectrila;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IT and IV or SC<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Leucovorin Calcium<br>* Given IV or PO<br>* Other names: Wellcovorin;Drug: Methotrexate<br>* Given IT, IV, and PO<br>* Other names: WR-19039;Drug: Mitoxantrone<br>* Given IV<br>* Other names: Mitozantrone;Drug: Mitoxantrone Hydrochloride<br>* Given IV<br>* Other names: Pralifan;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Therapeutic Hydrocortisone<br>* Given IT<br>* Other names: Rectoid;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm B (HR and IR blinatumomab)<br>Patients receive Blinatumomab Block 1 over 5 weeks, Blinatumomab Block 2 over 5 weeks, and then undergo allogeneic HSCT. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allogeneic HSCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Biological: Blinatumomab<br>* Given IV<br>* Other names: MT103;Drug: Cytarabine<br>* Given IT and IV or SC<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Methotrexate<br>* Given IT, IV, and PO<br>* Other names: WR-19039;Other: Pharmacological Study<br>* Correlative studies<br>Drug: Therapeutic Hydrocortisone<br>* Given IT<br>* Other names: Rectoid;|
| Active Comparator: Arm C (LR control)<br>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. | Drug: Asparaginase<br>* Given IM or IV<br>* Other names: Spectrila;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IT and IV or SC<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Leucovorin Calcium<br>* Given IV or PO<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT, IV, and PO<br>* Other names: WR-19039;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Pharmacological Study<br>* Correlative studies<br>Radiation: Radiation Therapy<br>* Undergo cranial radiation therapy<br>* Other names: Therapy, Radiation;Drug: Therapeutic Hydrocortisone<br>* Given IT<br>* Other names: Rectoid;Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm D (LR blinatumomab)<br>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. | Biological: Blinatumomab<br>* Given IV<br>* Other names: MT103;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IT and IV or SC<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Drug: Leucovorin Calcium<br>* Given IV or PO<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT, IV, and PO<br>* Other names: WR-19039;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Other: Pharmacological Study<br>* Correlative studies<br>Radiation: Radiation Therapy<br>* Undergo cranial radiation therapy<br>* Other names: Therapy, Radiation;Drug: Therapeutic Hydrocortisone<br>* Given IT<br>* Other names: Rectoid;Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine<br>* Given IV<br>* Other names: Vincrystine;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients | 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. | Up to 2 years from date of randomization | 
| Disease Free Survival (DFS) of Low Risk (LR) Relapse Patients | 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. | Up to 3 years from date of randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) of HR and IR Relapse Patients | 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. | Up to 2 years from date of randomization | 
| Overall Survival (OS) of LR Relapse Patients | 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. | Up to 3 years from date of randomization |