A Phase III Trial to Evaluate the Efficacy of the Addition of Inotuzumab Ozogamicin (a Conjugated Anti-CD22 Monoclonal Antibody) to Frontline Therapy in Young Adults (Ages 18-39 Years) With Newly Diagnosed Precursor B-Cell ALL
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 303
- 试验地点
- 831
- 主要终点
- EFS
研究概览
简要总结
This phase III trial studies the side effects of inotuzumab ozogamicin and how well it works when given with frontline chemotherapy in treating patients with newly diagnosed B acute lymphoblastic leukemia. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a chemotherapy drug called ozogamicin. Inotuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as CD22 receptors, and delivers ozogamicin to kill them. Chemotherapy drugs, such as [intervention], 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. Giving inotuzumab ozogamicin with chemotherapy may work better in treating young adults with B acute lymphoblastic leukemia.
详细描述
PRIMARY OBJECTIVES:
I. To confirm tolerability of the combination regimen with the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of cancer and leukemia group B (CALGB) 10403.
II. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, without censoring for transplant. (Phase III) III. To determine the safety and tolerability of a reduced dose of inotuzumab ozogamicin and two cycles of blinatumomab added to the pediatric-inspired regimen of CALGB 10403 (Pilor cohort).
SECONDARY OBJECTIVES:
I. To determine the impact of inotuzumab ozogamicin on disease-free (DFS) and overall survival (OS) in patients who achieve an induction response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 39 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1)
- •Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (WHO criteria) are eligible. Patients with Burkitt type ALL are NOT eligible
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Single-dose intrathecal cytarabine is allowed prior to registration or prior to initiation of systematic therapy for patient convenience; this is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture; systemic chemotherapy must begin within 72 hours of this intrathecal therapy
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Age >= 18 years and < 40 years
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Direct bilirubin =< 3 x upper limit of normal (ULN), unless suspected leukemic involvement of the liver
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Calculated (calc.) creatinine clearance >= 50 mL/min by Cockcroft-Gault
- •RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) CONFIRMATION OF TOLERABILITY AND PHASE III ONLY): Completion of remission induction therapy
- •RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) CONFIRMATION OF TOLERABILITY AND PHASE III ONLY):Patients with M2 marrow or better are eligible; patients with M3 or M4 marrow (greater than 25% lymphoblasts) will not be eligible to be randomized
- •Rating: M0, M1; Blast Cells (%): 0-5.0
- •Rating: M2; Blast Cells (%): 5.1-25.0
- •Rating: M3; Blast Cells (%): > 25-50
- •Rating: M4; Blast Cells (%): > 50.0
- •The term "blast cell" includes any cell that cannot be classified as a more mature normal element, and includes "leukemic cells," pathologic lymphocytes, and stem cells
- •RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) (CONFIRMATION OF TOLERABILITY AND PHASE III ONLY): Absolute neutrophil count (ANC) >= 750/mm^3
- •RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) (CONFIRMATION OF TOLERABILITY AND PHASE III ONLY): Platelet count >= 75,000/mm^3
- •RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) (CONFIRMATION OF TOLERABILITY AND PHASE III ONLY): Total bilirubin =< 1.5 x upper limit of normal (ULN), except for patients with known Gilbert's syndrome
- •RANDOMIZATION ELIGIBILITY CRITERIA (STEP 2) (CONFIRMATION OF TOLERABILITY AND PHASE III ONLY): Aspartate aminotransferase (AST) =< 8 x upper limit of normal (ULN)
排除标准
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients who have BCR-ABL fusion transcript determined by fluorescence in situ hybridization (FISH) or real time-polymerase chain reaction (RT-PCR) or t(9;22)(q34;q11) by cytogenetics are not eligible and should be considered for enrollment on studies that incorporate imatinib during induction; please note: patients must also be assessed for CD20 positivity and other markers; positivity for CD22 and CD20 is defined as baseline expression of the CD22 or CD20 antigen in more than 20% of leukemic cells using local multiparameter flow-cytometric immunophenotyping with the use of CD45 expression as a marker to gate the ALL blast population, according to recommendations from the European LeukemiaNet
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): No prior therapy for ALL except for limited treatment (=< 7 days) with corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine; however, patients who are being treated with chronic steroids for other reasons (for example, to treat asthma, autoimmune disorders, lupus, etc.) are eligible
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): No prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys; when indicated, leukapheresis or exchange transfusion is recommended to reduce the WBC
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Not pregnant and not nursing, because this study involves agents that have known genotoxic, mutagenic and teratogenic effects; therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 8 days prior to registration is required
- •REGISTRATION ELIGIBILITY CRITERIA (STEP 1): Patients with down syndrome are excluded from this study due to the likelihood of excessive toxicity resulting; these patients should be treated in consultation with a pediatric oncologist
研究组 & 干预措施
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Allopurinol (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Rituximab (Biological)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Dexamethasone (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Methotrexate (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Daunorubicin Hydrochloride (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Bone Marrow Aspiration and Biopsy (Procedure)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Cytarabine (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Dexamethasone (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Mercaptopurine (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Rituximab (Biological)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Pegylated L-Asparaginase (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Methotrexate (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Cyclophosphamide (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Doxorubicin (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Thioguanine (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Thioguanine (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Vincristine Sulfate (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Vincristine Sulfate (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Pegylated L-Asparaginase (Drug)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Cyclophosphamide (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Allopurinol (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Inotuzumab Ozogamicin (Biological)
Arm I (frontline chemotherapy)
See detailed description.
干预措施: Mercaptopurine (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Bone Marrow Aspiration and Biopsy (Procedure)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Daunorubicin Hydrochloride (Drug)
Arm II (frontline chemotherapy, inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin IV on days 1, 8, and 15 and undergo bone marrow aspirate and biopsy on day 28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who are MRD+ and CD19+ after completion of 2 cycles of inotuzumab ozogamicin receive dexamethasone IV or PO on day 1 and blinatumomab IV via continuous infusion on days 1-28, followed by a 14 day break. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive remission consolidated chemotherapy, interim maintenance chemotherapy, delayed intensification, and maintenance therapy as in Arm I. Patients undergo MUGA or echocardiography and x ray imaging during screening, bone marrow aspiration and biopsy and lumbar puncture and blood sample collection throughout the study.
干预措施: Cytarabine (Drug)
结局指标
主要结局
EFS
时间窗: Time from induction response to the time of progressive-disease, secondary malignancy, or death, assessed up to 3 years
Will be compared using log-rank tests. EFS curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model. The corresponding hazard ratio, 2- and 3-year EFS estimates will be assessed, and EFS medians along with their 95% confidence intervals for the two treatment arms.
Event-free survival (EFS)
时间窗: Time from induction response to the time of progressive-disease, secondary malignancy, or death, assessed up to 3 years
The EFS distributions between the two arms will be compared using non-stratified log-rank tests. EFS curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model. with diagnostics test on proportional hazard assumptions first. The corresponding hazard ratio, 2- and 3-year EFS estimates will be assessed, and EFS medians along with their 95% confidence intervals for the two treatment arms.
次要结局
- Proportion of patients who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial(Up to 10 years)
- Overall induction response rates(Up to 10 years)
- Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events version 4.0(Up to 10 years)
- Proportion of patients who achieve CR or any response to induction therapy(Up to 10 years)
- Proportion of patients who go off treatment due to adverse reactions(Up to 10 years)
- OS(Time from randomization to the time of death due to any cause, assessed up to 10 years)
- DFS(Time from achievement of CR to the time of relapse and/or death, assessed up to 10 years)
- Disease-free survival (DFS)(Time from achievement of complete response (CR) to the time of relapse and/or death, assessed up to 10 years)
- Overall Survival (OS)(Time from randomization to the time of death due to any cause, assessed up to 10 years)
- Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events version 5.0(Up to 10 years)