临床试验/NCT05192889

NCT05192889进行中（未招募）1 期

RAVEN: A Phase I/II Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax

St. Jude Children's Research Hospital2 个研究点分布在 1 个国家目标入组 35 人开始时间: 2022年8月25日最近更新: 2025年9月22日

适应症

干预措施

试验速览

阶段: 1 期
状态: 进行中（未招募）
发起方: St. Jude Children's Research Hospital
入组人数: 35
试验地点: 2
主要终点: Number of Participants With Minimal Residual Disease (MRD)-Negative Response

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a phase I/II clinical trial evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) and assessing the combination dose of venetoclax combinations with either blinatumomab for CD19-positive patients or navitoclax and high-dose cytarabine for CD19-negative patients.

Primary Objectives

To compare Minimal Residual Disease (MRD)-negative CR/CRi rate in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL) following Block 1 therapy with venetoclax and navitoclax based reinduction to historical controls.
To identify the recommended phase 2 combination dose (RP2D) of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.

Secondary Objectives

To estimate the tolerability and activity of venetoclax based consolidation in novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.
To describe event-free and overall survival in patients treated with this regimen.

Exploratory Objectives

To evaluate MRD-negative CR/CRi rates in each prespecified groups: late first relapse B-ALL; early first relapse and second or greater relapse B-ALL; and relapsed T-ALL.
To identify drug sensitivity patterns in patient samples prior to and after receiving combination therapy and evaluate mechanisms of disease resistance/ escape.
To explore immune subsets during and after this regimen.
Evaluate response to therapy in rare relapse patient subsets.
Explore breakthrough infections in children and young adults with relapsed or refractory ALL

详细描述

This is a non-randomized phase I/II clinical trial. In Block I, all patients receiving common therapy evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL).

In Block 2, a phase 1 rolling six design and phase 2 extension will be used to assess the combination dose of venetoclax combinations with either blinatumomab for CD19-positive patients or navitoclax and high-dose cytarabine for CD19-negative patients. One to six participants can be concurrently enrolled onto a dose level, depending on the number of participants enrolled at the current dose level, the number of participants who have experienced a dose/combination limiting toxicity (DLT) at the current dose level, and the number of participants entered but with tolerability data pending. Dose de-escalation will occur if 2 patients at a dose level experience a targeted toxicity. If 6 patients complete a therapy block and experience 0-1 DLT, that dose will be considered the recommended phase 2 dose (RP2D). New enrollment on an arm (2a/2b) will be paused if further enrollment would result in more than 6 patients being treated on that arm before the RP2D is identified.

The primary outcome assessment will be a bone marrow with MRD testing on Day 29 of Block 1 therapy. Following that assessment, patients should continue with protocol therapy including either Block 2A (which includes high-dose cytarabine with venetoclax and navitoclax) for patients with CD19 negative leukemia, those with isolated extramedullary relapse, or whose treating physician determines that blinatumomab therapy is not in the patient's best interest; or Block 2B for patients with leukemia which is CD19 positive. Following recovery from Block 2 therapy, all patients except those with late first relapse of B-ALL (≥ 36 months from diagnosis) who are MRD-negative at <0.01% after Block 1 therapy are off therapy. Further therapy for these patients is at the treating physician's discretion. Patients with late first relapse B-ALL relapse and who are MRD negative will proceed with intensification, interim continuation, and continuation therapy. Patients with Down's Syndrome with CD19 negative leukemia will be off therapy after Block 1 as they are ineligible for Block 2A. Patients in exploratory cohorts I and N who are late first relapse B-ALL and who are MRD-negative after Block 1 therapy may continue on protocol therapy after Block 2 or receive alternative therapy at their treating physician's discretion. Patients in exploratory cohort M and O are off therapy after Block 2.

Intervention:

Block 1 Therapy:

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Sequential
主要目的: Treatment
盲法: None

入排标准

年龄范围: 4 Years 至 30 Years（Child, Adult）
性别: All
接受健康志愿者: 否

入选标准

•Diagnosis:
•Relapsed or refractory acute lymphoblastic leukemia or lymphoma with ≥1% bone marrow disease as measured by flow cytometry, PCR, or next generation sequencing. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood.
•Patients with 1-4.99% bone marrow involvement must have disease confirmed in one of the following ways: an alternative minimal residual disease assay (e.g. flow cytometry and PCR or NGS), cytogenetic abnormality consistent with patient's leukemia, FISH abnormality, or a second bone marrow with MRD ≥1% separated by 1-4 weeks.
•Patients with ≥5% bone marrow disease by a single measurement as measured by flow cytometry, PCR, or next generation sequencing do not require a second confirmatory test.
•Refractory disease is defined as residual leukemia ≥1% after at least 2 prior lines of frontline therapy with curative intent.
•Patients in exploratory cohort I must have measurable extramedullary disease but may have <1% bone marrow disease.
•Patients in exploratory cohort M must have ≥1% bone marrow disease as measured by flow cytometry of mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL).
•Age ≥4 to < 30 years. Patients ≥ 22 years old are only eligible for exploratory cohort O. Sites may have different (lower) maximum ages based on institutional guidelines but may not exceed 30 years.
•Patient weighs ≥ 20 kg.
•Patient is able to swallow pills.
•Lansky/Karnofsky score is ≥ 60%. The Lansky performance score should be used for participants < 16 years and the Karnofsky performance score for participants ≥ 16 years.
•Participant has adequate organ function as defined by the following:
•Direct bilirubin ≤ 1.5x the institutional upper limit of normal (ULN) unless attributable to leukemic involvement. At institutions which do not obtain a direct bilirubin in patients with a normal total bilirubin, a normal total bilirubin may be used as evidence that the direct bilirubin is not > 1.5x the ULN. Patients with a direct bilirubin ≥ 2 mg/dl may not enroll regardless of attribution.
•Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x the ULN unless increase is attributable to leukemic involvement.
•Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73 m^
•Left ventricular ejection fraction (LVEF) ≥ 40% or shortening fraction ≥ 25%.
•Patients with a history of reduced LVEF which subsequently improved with medical management are eligible if they meet the criteria above.
•Patients must have fully recovered from the acute effects of all prior therapy (defined as resolution of all such toxicities to ≤ Grade 2).
•For patients with prior hematopoietic stem cell transplant (HSCT), at least 90 days must have elapsed since transplant, the patient cannot have evidence of active graft-versus-host disease (GVHD), and they must be off calcineurin inhibitors for ≥4 weeks, and off other immunosuppression for ≥2 weeks.
•Patients with Down Syndrome/ germline Trisomy 21 are eligible for Block 1 and Block 2b therapies but are ineligible for Block 2a therapy. Patients with Down Syndrome and CD19-negative disease are off therapy after the response evaluation to Block
•Prior therapy
•≥14 days must have elapsed since the completion of cytotoxic therapy, with the exception of standard maintenance therapy (glucocorticoids, vincristine, methotrexate, 6-mercaptopurine), tyrosine kinase inhibitors, and steroids.
•Cytoreduction with prednisone, methylprednisolone, or hydroxyurea for ≤ 120 hours (5 days) in patients with hyperleukocytosis or extramedullary disease compromising organ function can be initiated and continued until up to 24 hours prior to the start of protocol therapy.
•At least 21 days must have elapsed since completion of therapy with a biologic agent excluding blinatumomab. For agents that have known adverse events occurring beyond 21 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur. At least 7 days must have elapsed since blinatumomab infusion and patients must have recovered from all toxicities as described above.
•Intrathecal cytotoxic therapy: No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone. Intrathecal chemotherapy given at the time of diagnostic LP to evaluate for relapse prior to study enrollment is allowed.
•Patient has not had prior exposure to navitoclax
•Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment.
•Additional criteria for exploratory cohorts
•Cohort I: Diagnosis of isolated extramedullary relapse as defined by bone marrow blasts of <1% AND 1) central nervous system white blood cell count (WBC) of ≥ 5WBC/mL with blasts or 2) biopsy confirmed extramedullary leukemia.
•Cohort M: Diagnosis of relapsed or refractory mixed phenotype acute leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL).
•Cohort N: Patients with relapsed or refractory ALL who, in the view of the provider, are unable to tolerate further asparaginase therapy due to prior toxicities.
•Cohort O: Patients with relapsed or refractory ALL who are ages 22-29.9 years. This cohort may not enroll patients at all sites based on institutional guidelines or capacity.

排除标准

•Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
•Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment).
•Concomitant medications and food:
•Treatment with moderate or strong cytochrome P450 3A (CYP3A) inhibitors within 3 days of starting protocol therapy.
•Treatment with moderate or strong CYP3A inducers within 7 days of starting protocol therapy.
•Administration or consumption within 3 days prior to the first dose of study drug or grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit.
•Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

研究组 & 干预措施

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Venetoclax (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Navitoclax (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Dexamethasone (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Vincristine (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Calaspargase Pegol (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Dasatinib (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Leucovorin (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Intrathecal Triples (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Pegaspargase (Drug)

Block 1

Experimental

All eligible patients receive intervention according to the Detailed Description section with the following:

Venetoclax, Navitoclax, Dexamethasone, Vincristine, Calaspargase Pegol, Pegaspargase, Erwinia asparaginase, Dasatinib, Leucovorin, Intrathecal (IT) MHA (methotrexate/hydrocortisone/cytarabine)

干预措施: Erwinia asparaginase (Drug)