A Phase II Randomized Study of Blinatumomab With or Without Revumenib for Patients With KMT2A-Translocation B-Cell Acute Lymphoblastic Leukemia (ALL)/ Acute Leukemia With Ambiguous Lineage (ALAL) With Persistent Measurable Residual Disease (MRD)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 90
研究概览
简要总结
This phase II trial tests how well adding revumenib to usual treatment (blinatumomab) compared to usual treatment alone works in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) or acute leukemia with ambiguous lineage (ALAL) with KMT2A-translocation. Revumenib binds to a protein called menin and keeps it from binding to another protein called KMT2A. This stops or slows the growth of leukemia cells with changes in the KMT2A gene. Blinatumomab binds to CD19, which is found on most B cells (a type of white blood cell) and some types of leukemia cells. It also binds to a protein called CD3, which is found on T cells (another type of white blood cell). This may help the immune system kill cancer cells. In addition to blinatumomab, usual treatment also includes dexamethasone, methotrexate, cyclophosphamide, cytarabine, mercaptopurine, calaspargase pegol, doxorubicin, thioguanine, daunorubicin, vincristine and leucovorin. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Methotrexate is in a class of medications called antimetabolites. It is also a type of antifolate. Methotrexate stops cells from using folic acid to make deoxyribonucleic acid (DNA) and may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Chemotherapy drugs, such as cytarabine, mercaptopurine, calaspargase pegol, doxorubicin, thioguanine, and daunorubicin, 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. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Leucovorin is also being studied in the treatment of cancer. It is a type of chemoprotective agent and a type of chemosensitizing agent. Adding revumenib to usual treatment with blinatumomab may be safe, tolerable and more effective than blinatumomab alone in lowering the amount of leukemia in patients with B-ALL or ALAL with the KMT2A translocation.
详细描述
PRIMARY OBJECTIVES:
I. Among participants enrolled to the safety run-in cohort, to evaluate the safety of blinatumomab with revumenib in this participant population. (Cohort A: Children [≥ 1 year] and adults with CD19-positive [CD19+] KMT2Ar B-cell acute lymphoblastic leukemia [ALL]/ acute leukemia with ambiguous lineage [ALAL] in morphological first complete remission [CR1]) II. First primary randomized objective: Among participants with positive measurable residual disease (MRD) by clonoSEQ before randomization, to compare the rates of MRD negative complete remission (CR) by clonoSEQ after the completion of one cycle of blinatumomab versus one cycle of blinatumomab plus revumenib. (Cohort A: Children [≥ 1 year] and adults with CD19-positive [CD19+] KMT2Ar B-cell acute lymphoblastic leukemia [ALL]/ acute leukemia with ambiguous lineage [ALAL] in morphological first complete remission [CR1]) III. Secondary primary randomized objective (hierarchical tested): Among participants with positive MRD by clonoSEQ before randomization, if rates of MRD negative CR by clonoSEQ after completion of one cycle of therapy are improved with blinatumomab plus revumenib versus blinatumomab, to evaluate whether MRD-event-free survival is improved among patients randomized to blinatumomab plus revumenib versus blinatumomab. (Cohort A: Children [≥ 1 year] and adults with CD19-positive [CD19+] KMT2Ar B-cell acute lymphoblastic leukemia [ALL]/ acute leukemia with ambiguous lineage [ALAL] in morphological first complete remission [CR1]) IV. To describe and evaluate the feasibility of revumenib in combination with reduced intensity multiagent chemotherapy in this participant population. (Cohort B: Untreated newly diagnosed KMT2Ar B/T-ALL or ALAL in older adults [age ≥ 55 years])
SECONDARY OBJECTIVES:
I. Within each arm and cohort and across cycles of therapy, to estimate the frequency and severity of toxicities.
II. In Cohort A: Among participants with positive MRD by clonoSEQ before randomization, to estimate the rate of MRD negative CR by clonoSEQ after two cycles of blinatumomab or blinatumomab plus revumenib.
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
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •COHORT A: Participants must meet diagnostic criteria for either B-cell acute lymphoblastic leukemia (ALL) with KMT2A-translocation or acute leukemia with ambiguous lineage (ALAL) with KMT2A-translocation
- •COHORT A: Participants must have KMT2A-translocation documented locally by conventional cytogenetics, fluorescence in situ hybridization (FISH) or molecular studies such as next generation sequencing (NGS)
- •COHORT A: Participants must have achieved morphological first complete remission (CR1) after induction cycle (s) as defined bone marrow lymphoblasts < 5%
- •COHORT A: Participants must have either known trackable clone(s) by clonoSEQ that was identified at initial diagnosis, or a banked diagnostic sample, which can include clinical samples from the treating institution, available that can be used to identify trackable clone(s)
- •Participants must not be known not to have trackable clones by clonoSEQ
- •Participants must not be known already to have MRD-negativity by clonoSEQ prior to enrollment
- •COHORT A: Participants must have evidence of CD19 expression at any level in ALL or ALAL documented locally by flow cytometry or immunohistochemistry in bone marrow or peripheral blood at the time of initial diagnosis. Immunophenotyping of the blood or marrow lymphoblasts must be performed to determine lineage. Appropriate marker studies including CD19 (B cell) must be performed. If a bone marrow aspirate cannot be obtained despite an attempt (dry tap), appropriate Immunohistochemistry (IHC) testing, including CD19, must be performed on the bone marrow biopsy to determine lineage
- •COHORT A: Participants must have Philadelphia-chromosome negative ALL or ALAL
- •COHORT A: Participants must not have known lymphoid blast crisis arising from chronic myeloid leukemia (CML) or have received previous tyrosine kinase inhibitor (TKI) therapy for their chronic myeloid leukemia (CML)
- •COHORT B: Participants must meet diagnostic criteria for either newly diagnosed with acute lymphoblastic leukemia (ALL) or acute leukemia with ambiguous lineage (ALAL)
- •Participants with either B or T-cell subtypes of ALL are permitted on Cohort B
- •Participants must have KMT2A-translocation documented locally by conventional cytogenetics, fluorescence in situ hybridization (FISH) or molecular studies such as next generation sequencing (NGS)
- •COHORT B: Participants must have Philadelphia-chromosome negative ALL or ALAL
- •COHORT B: Participants must not have known lymphoid blast crisis arising from CML or have received previous TKI therapy for their chronic myeloid leukemia (CML)
- •COHORT A: Participants ≥ 18 years may have received 1 to 3 cycles of induction/consolidation before entering the study. It is encouraged to enroll participants immediately after completing the first induction cycle if the patient achieves morphological CR. For pediatric patients < 18 years of age, enrollment must occur after induction therapy
- •COHORT A: Participants must discontinue strong cytochrome P450 (CYP)3A4 inhibitors or strong or moderate inducers, except corticosteroids, within 14 days prior to registration
- •COHORT A: Participants must have recovered from any prior major surgery adverse effects at least 14 days prior to registration, to the satisfaction of the local investigator
- •Note: Central venous access placement is not considered major surgery for the purposes of this protocol
- •COHORT A: Participants must not be receiving any oral or intravenous systemic immunosuppressive therapy with the exception of induction/consolidation chemotherapy for the treatment of their current ALL or ALAL. Participants may receive up to 10 mg per day of prednisone or prednisone equivalent for adrenal insufficiency or other indications
- •COHORT A: Participants must not have received a prior allogeneic hematopoietic stem cell transplant
- •COHORT A: Participants must not have received prior blinatumomab, menin inhibitors, chimeric antigen receptor (CAR)-T therapy, or anti-CD19 antibodies
- •COHORT B: Participants must not have received prior systemic therapy for ALL or ALAL, with the exception of hydroxyurea, steroid, retinoic acid, intrathecal chemotherapy, or induction chemotherapy as defined below
- •Participants who have been started on the study regimen backbone (i.e. induction therapy) before consenting and then are found to have the KMT2Ar and are eligible for the study, can be enrolled on the study as long as revumenib treatment can be started by day 8 of induction therapy
- •COHORT B: Participants must discontinue strong CYP3A4 inhibitors or strong or moderate inducers, except corticosteroids, within 14 days prior to registration
- •COHORT B: Participants must have recovered from any prior major surgery adverse effects at least 14 days prior to registration, to the satisfaction of the local investigator
- •Note: Central venous access placement is not considered major surgery for the purposes of this protocol
- •COHORT B: Participants must not be receiving any systemic oral or intravenous immunosuppressive therapy with the exception of induction chemotherapy or corticosteroid for the treatment of their current ALL or ALAL
- •COHORT B: Participants must not have received a prior allogeneic hematopoietic stem cell transplant
- •COHORT A: Participant must be ≥ 1 years old at the time of registration. There is no upper age limit
- •COHORT A: Participant must have Zubrod/Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or Lansky/Karnofsky performance status scores of 50-100
- •COHORT A: Participants must have a complete medical history and physical exam within 28 days prior to registration
- •COHORT A: Glomerular filtration rate (GFR) ≥ 50 ml/min/1.73 m^2 (within 14 days prior to registration)
- •COHORT A: Absolute neutrophil count ≥ 1 x 10^3/uL (within 14 days prior to registration)
- •COHORT A: Platelets ≥ 100 x 10^3/uL (within 14 days prior to registration)
- •COHORT A: Direct bilirubin ≤ 2.0 mg/dL (34.2 micromoles/L) (within 14 days prior to registration)
- •Note: Participants with history of Gilbert's disease must have direct bilirubin ≤ 5 x institutional upper limit of normal (ULN)
- •COHORT A: Alanine aminotransferase (ALT) ≤ 5 x institutional ULN (within 14 days prior to registration)
- •COHORT A: Participants ≥ 18 years must have a calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 14 days prior to registration
- •COHORT A: Adequate renal function for participants < 18 years of age is defined as:
- •A GFR ≥ 50 mL/min/1.73 m^2, as determined by one of the following methods:
- •Estimated GFR (eGFR) ≥ 50 mL/min/1.73 m^2 "Bedside" Schwartz formula (2009)
- •Measured GFR ≥ 50 mL/min/1.73 m^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard)
- •COHORT A: Participants must have adequate cardiac function. Participants must have cardiac ejection fraction ≥ 50% by MUGA or 2 dimensional (2-D) echocardiogram or shortening fraction (SF) ≥ 27% by echocardiogram within 90 days prior to registration. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
- •COHORT A: Participants ≥ 18 years of age with a known history of human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
- •COHORT A: Participants ≥ 18 years of age with a known history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated
- •COHORT A: Participants ≥ 18 years of age with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated
- •COHORT A: Participants must not have prolonged Fridericia's formula-corrected QT interval (QTcf) defined as > 450 msec on screening electrocardiogram (EKG) prior to registration
- •COHORT A: Participants must not have relapsed or refractory disease in the bone marrow (≥ 5% blasts) or extramedullary sites involvement
- •COHORT A: Participants must not have systemic fungal, bacterial, viral or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) as determined by the local investigator
- •COHORT A: Participants must not have clinically significant autoimmune disease
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排除标准
- 未提供