A Phase 3 Randomized Trial of Inotuzumab Ozogamicin (IND#:133494, NSC#: 772518) for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Post-Induction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and Disseminated B-LLy
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 5,951
- 试验地点
- 413
- 主要终点
- Post-induction 5-year event-free survival (EFS)
研究概览
简要总结
This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy and immunotherapy (chemo-immunotherapy) for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. Inotuzumab ozogamicin is a monoclonal antibody, which is a type of protein that can bind to certain targets on the surface of cells. Inotuzumab ozogamicin is a monoclonal antibody that is linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells by binding to the CD22 protein on the surface of the cancer cell and delivering calicheamicin inside the cells to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase or calaspargase pegol 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. Blinatumomab is a specialized type of monoclonal antibody known as a bispecific T-cell engager (BiTE). It works by simultaneously binding to CD19 on cancer cells and CD3 on normal immune cells, bringing them together to destroy leukemia cells. Blinatumomab is a standard part of chemo-immunotherapy treatment for B-ALL. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin or blinatumomab.
The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemo-immunotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first phase of therapy: Induction. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-induction treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (consolidation, blinatumomab block 1, interim maintenance 1, blinatumomab block 2, delayed intensification, interim maintenance 2, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of consolidation or part of delayed intensification. Other aims of this study include evaluating 1) side effects of treatment using patient-reported outcomes and health-related quality of life, 2) the best ways to help patients adhere to oral chemotherapy regimens, 3) the relationship between levels of inotuzumab ozogamicin in the blood and side effects, 4) the impact of chemo-immunotherapy on the immune system and risk of infection, and 5) the impact of social determinants of health on outcomes. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.
详细描述
PRIMARY OBJECTIVE:
I. To compare in a randomized manner the post-induction 5-year event-free survival (EFS) for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with a modified Berlin-Frankfurt-Münster (mBFM) chemo-immunotherapy backbone that includes blinatumomab and replaces Consolidation Part 2 and Delayed Intensification (DI) Part 2 with two blocks of inotuzumab ozogamicin, versus those treated with a full mBFM chemo-immunotherapy backbone that includes blinatumomab and retains Consolidation Part 2 and DI Part 2 without the addition of inotuzumab ozogamicin.
SECONDARY OBJECTIVES:
I. To describe the 5-year disease-free survival (DFS) for a favorable risk subset of National Cancer Institute (NCI) HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex. (Pre-Amendment #7B) II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL, including toxicity experienced during phases of therapy subsequent to inotuzumab ozogamicin.
III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi intravenous (IV) methotrexate without leucovorin rescue plus pegaspargase or calaspargase pegol (C-MTX).
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
- 365 Days 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility studies (Part A) prior to treatment and enrollment on AALL
- •Note that central confirmation of MPAL diagnosis must occur within 22 days of enrollment for suspected MPAL patients. If not performed within this time frame, patients will be taken off protocol.
- •APEC14B1 is not a requirement for B-LLy patients but for institutional compliance every patient should be offered participation in APEC14B
- •B-LLy patients may directly enroll on AALL
- •Patients must be > 365 days and < 25 years of age
- •Initial white blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to the start of protocol-directed systemic therapy):
- •Age 1-9.99 years: WBC >= 50,000/uL
- •Age 10-24.99 years: Any WBC
- •Age 1-9.99 years: WBC < 50,000/uL with one or more of the following:
- •Testicular leukemia
- •CNS leukemia (CNS3)
- •Steroid pretreatment.
- •Initial white blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to the start of protocol-directed systemic therapy):
- •Age 1-24.99 years: any WBC NOTE: Patients enrolled as suspected MPAL but found on central confirmatory testing to have B-ALL must meet the B-ALL criteria above (age, WBC, extramedullary disease, steroid pretreatment) to switch to the B-ALL stratum before the end of induction.
- •Patient has newly diagnosed B-ALL or MPAL (by World Health Organization [WHO] 2016 criteria) with >= 25% blasts on a bone marrow (BM) aspirate;
- •OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM biopsy;
- •OR A complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells if a bone marrow aspirate or biopsy cannot be performed.
- •Patient has newly diagnosed B-LLy Murphy stages III or IV.
- •Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment.
- •Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted.
- •Central nervous system (CNS) status must be determined prior to enrollment based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment and cytoreduction. Note that once cerebrospinal fluid (CSF) has been collected, protocol therapy can be initiated while final determination of CNS status is pending. It is recommended that intrathecal cytarabine be administered at the time of the diagnostic lumbar puncture. This is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture. This is allowed prior to enrollment. Systemic chemotherapy must begin within 72 hours of this intrathecal therapy.
- •Direct bilirubin < 2.0 mg/dL (34 micromoles/L)
- •Alanine aminotransferase (ALT) ≤ 10x upper limit of normal (ULN). For the purposes of this study, the ULN for ALT is defined as 45 U/L
- •Exceptions to this include patients with known Gilbert's Syndrome, or those with hepatic involvement from leukemic or lymphomatous infiltration
- •All patients and/or their parents or legal guardians must sign a written informed consent.
- •All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met.
排除标准
- •Patients with Down syndrome are not eligible
- •With the exception of steroid pretreatment and steroid cytoreduction or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL
- •Patients who have received > 72 hours of hydroxyurea within one week prior to start of systemic protocol therapy.
- •Patients with B-ALL or MPAL who do not have sufficient diagnostic bone marrow submitted for APEC14B1 testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
- •Patients with acute undifferentiated leukemia (AUL) are not eligible.
- •For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid pretreatment, the following additional exclusion criteria apply:
- •T-lymphoblastic lymphoma.
- •Morphologically unclassifiable lymphoma.
- •Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
- •Patients with known Charcot-Marie-Tooth disease.
- •Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
- •Patients requiring radiation at diagnosis.
- •Female 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.
- •Lactating women who plan to breastfeed their infants while on study and for 2 months after the last dose of inotuzumab ozogamicin.
- •Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of study participation. For those patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the last dose of inotuzumab ozogamicin for females and 5 months after the last dose of inotuzumab ozogamicin for males.
研究组 & 干预措施
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Daunorubicin Hydrochloride (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Dexamethasone (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Bone Marrow Aspiration (Procedure)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Cytarabine (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Bone Marrow Biopsy (Procedure)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Calaspargase Pegol (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Cyclophosphamide (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Cytarabine (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Mercaptopurine (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Leucovorin Calcium (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Cyclophosphamide (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Pegaspargase (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Prednisone (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Cytarabine (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Daunorubicin Hydrochloride (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Thioguanine (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Methotrexate (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Biospecimen Collection (Procedure)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Questionnaire Administration (Other)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Bone Marrow Biopsy (Procedure)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Questionnaire Administration (Other)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Questionnaire Administration (Other)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Cytarabine (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Dexamethasone (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Biospecimen Collection (Procedure)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Blinatumomab (Biological)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Calaspargase Pegol (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Vincristine Sulfate (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Blinatumomab (Biological)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Pegaspargase (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Prednisolone (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Prednisone (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Radiation Therapy (Radiation)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Bone Marrow Aspiration (Procedure)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Radiation Therapy (Radiation)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Bone Marrow Aspiration (Procedure)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Bone Marrow Biopsy (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Bone Marrow Biopsy (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Bone Scan (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Computed Tomography (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Vincristine Sulfate (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Cyclophosphamide (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Prednisolone (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Prednisone (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Mercaptopurine (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Dexamethasone (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Thioguanine (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Dexamethasone (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Leucovorin Calcium (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Leucovorin Calcium (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Radiation Therapy (Radiation)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Biospecimen Collection (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Radiation Therapy (Radiation)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Mercaptopurine (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Methotrexate (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Vincristine Sulfate (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Daunorubicin Hydrochloride (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Prednisone (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Mercaptopurine (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Biospecimen Collection (Procedure)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Bone Marrow Aspiration (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Positron Emission Tomography (Procedure)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Questionnaire Administration (Other)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Daunorubicin Hydrochloride (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Calaspargase Pegol (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Methotrexate (Drug)
Arm D (CD 22 positive HR B-ALL)
See detailed description for Arm D.
干预措施: Calaspargase Pegol (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Cyclophosphamide (Drug)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Inotuzumab Ozogamicin (Biological)
Arm E (CD22 positive HR B-ALL)
See detailed description for Arm E.
干预措施: Pegaspargase (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Methotrexate (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Pegaspargase (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Prednisolone (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Thioguanine (Drug)
Arm I (MPAL)
See Detailed Description for Arm I.
干预措施: Vincristine Sulfate (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Leucovorin Calcium (Drug)
Arm II (B-LLy)
See Detailed Description for Arm II.
干预措施: Prednisolone (Drug)
结局指标
主要结局
Post-induction 5-year event-free survival (EFS)
时间窗: From study entry to first event (induction failure, induction death, end of induction [EOI] minimal residual disease [MRD] ≥ 5%,EO consolidation [C] MRD ≥ 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years
Will compare in a randomized manner the post-induction 5-year EFS for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with a modified Berlin-Frankfurt-Münster (mBFM) chemo-immunotherapy backbone that includes blinatumomab and replaces Consolidation Part 2 and Delayed Intensification (DI) Part 2 with two blocks of inotuzumab ozogamicin, versus those treated with a full mBFM chemo-immunotherapy backbone that includes blinatumomab and retains Consolidation Part 2 and DI Part 2 without the addition of inotuzumab ozogamicin.
次要结局
- Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL(Up to 5 years)
- 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX(From study entry to first event (progressive disease, induction death, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years)
- 5-year DFS for favorable risk subset of NCI HR B-ALL (HR favorable) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD MTX) Interim Maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex(From EOC to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years)
- 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous MTX without leucovorin rescue+pegaspargase or calaspargase pegol(From study entry to first event (induction failure, Induction death, end of induction (EOI) minimal residual disease (MRD) >= 5%, EOC MRD >= 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years)
- Health-related quality of life (HRQoL) for HR B-ALL(Consolidation Part 2 Day 43 (Arm D)/Inotuzumab ozogamicin Block 1 Day 15 (Arm E) up to Day 1 of IM2 (Arms D and E))
- Incidence of symptomatic AEs for patients with HR B-ALL(Up to 5 years)