A Phase 3, Multicenter Trial for Pediatric Philadelphia Chromosome-positive B-Acute Lymphoblastic Leukemia -2025 Project
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 150
- 试验地点
- 23
- 主要终点
- Day 48 end-of-induction measurable residual diseases (MRD48) after induction remission with olverembatinib and blinatumomab, compared to MRD46 of those treated with dasatinib plus chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts .
研究概览
简要总结
This prospective clinical trial evaluates the effectiveness and safety of "chemotherapy-light" regimen incorporating the third-generation TKI olverembatinib, the bi-specific CD3/CD19 T cell engager blinatumomab, and the BCL-2 selective inhibitor venetoclax for newly diagnosed pediatric/adolescent patients with Ph+ ALL. The CCCG-Ph+ B-ALL-2025 protocol will be modified as following compared to the CCCG-ALL-2020 protocol
详细描述
- All Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen.
- OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol.
- Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity.
- All patients will receive two cycles of HDMTX+Blina-14 and 4 times of triple intrathecal therapy (TIT) throughout the consolidation 1 phase.
- To decrease the toxicities of high-dose AraC, the dosage will be reduced to 1 g/m2 in the consolidation 2 phase in contrast to 2 g/m2 in 2020 protocol.
- Throughout the early Maintenance Therapy, dexamethasone and vincristine combination will be added with either venetoclax or daunorubicin alternatively for five cycles, given after MTX and 6-MP.
- Cyclophosphamide and asparaginase are totally omitted from the entire treatment to mitigate toxicities.
- Olverembatinib concentrations are recommended to be examined (cerebrospinal fluid and peripheral blood in parallel) before OVB given, after full dosing of OVB, and/or Blina+OVB, best to match lumbar puncture assessments timepoints.
- IgH rearrangement by NGS MRD will be added as an evaluation indicator, with testing frequency matching bone marrow aspiration assessments.
- Pharmarcotyping studies are recommended at baseline if condition permits.
- For patients who cannot use full-dose blinatumomab, we will adopt the CCCG-Ph+ALL2020 protocol. complications.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Month 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must meet all items below:
- •Age older than 1 month to younger 18 years.
- •Newly diagnosed Philadelphia chromosome-positive or BCR::ABL1-positive B-ALL.
- •Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.
排除标准
- •Should be excluded if had any item below:
- •ALL evolved from CML.
- •Known underlying congenital immunodeficiency or metabolic disease.
- •Congenital heart disease with cardiac insufficiency.
- •Gastrointestinal dysfunction or gastrointestinal diseases that may significantly alter the absorption of study drug.
- •Severe malnutrition, uncontrolled active infections, or serious cardiovascular diseases.
- •Subjects with significant CNS disorder (e.g., uncontrolled seizure disorder, autoimmune disease involving CNS).
- •Treated with glucocorticoids for ≥14 days, or targeted inhibitor for > 7 days within one month before enrollment, or any chemotherapy or any systemic anticancer therapy (including but not limited to any TKI) or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression).
- •Any significant comorbidities or psychiatric disorders that may impact patient safety, compliance, informed consent, study participation, follow-up, or the interpretation of study results. In such cases, all participating sites must report directly to the PI to determine whether the patient meets exclusion criteria.
研究组 & 干预措施
OVB+Blina+VEN+Chemo-light regimen
All Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen. Cyclophosphamide and asparaginase are totally omitted from the entire treatment to mitigate toxicities.
OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol.
Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity.
All patients will receive two cycles of HDMTX+Blina-14 and 4 times of triple intrathecal therapy (TIT) throughout the consolidation 1 phase. The dosage of AraC will be reduced to 1 g/m2 in the consolidation 2 phase.
Throughout the early Maintenance Therapy, dexamethasone and vincristine combination will be added with either venetoclax or daunorubicin alternatively for five cycles, given after MTX and 6-MP.
干预措施: olverembatinib (Drug)
结局指标
主要结局
Day 48 end-of-induction measurable residual diseases (MRD48) after induction remission with olverembatinib and blinatumomab, compared to MRD46 of those treated with dasatinib plus chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts .
时间窗: Up to approximately 4.5 years.
Primary analysis will be performed by one-sided (Monte-Carlo-) exact chi-square test because the objective calls for testing if the proportion of patients in the \<0.01% Day 48 MRD group is higher than the historical control. The historical control of Day 46 MRD of dasatinib combination with intensive chemotherapy is 80%. It is estimated that VPO+Blinatumomab can increase the negative rate of Day 48 MRD by 10%. a total sample size of 135 provides sufficient power for the planned analyses outlined above if the true D48 MRD negativity probability is 0.90 or higher based on a one-sided alpha of 0.05.
次要结局
- Day 19 measurable residual diseases (MRD19) during induction remission with olverembatinib plus VP (VOP), compared to MRD19 of those treated with dasatinib plus 4-drug chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts(Approximately 4.5 years.)
- Event-free survival (EFS) of patients treated with this therapy, in comparison to historical regimens.(Approximately 7 years.)
- Overall survival (OS) of patients treated with this therapy, in comparison to historical regimens(Approximately 7 years.)
- Cumulative incidence of relapse (CIR) of this therapy, in comparison to historical regimens.(Approximately 7 years.)