Efficacy of Low-dose Venetoclax With Itraconazole + TACL in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Overall response rata after low dose venetoclax with itraconazole plus TACL
研究概览
简要总结
Relapsed/refractory acute lymphoblastic leukemia remains a challenge in the context of limited access to immunotherapy in developing countries. With such poor 5-year overall survival rates of 10%, the investigators need strategies that surpass the complete response rate achieved in this setting, which does not exceed 60% effectiveness with different regimens, and to eventually transfer patients to hematopoietic stem cell transplantation.
In this context, the investigators are studyng if the use of venetoclax, a BCL2 inhibitor, with the use of a cytochrome p450 inhibitor such as itraconazole, alongside the TACL chemotherapy regimen, which is based on the combination of asparaginase, dexamethasone, bortezomib, vincristine, and mitoxantrone.
详细描述
Response rates for salvage regimens vary depending on the patient's performance status (suitable or unsuitable for high-intensity chemotherapy), whether the patient is refractory (40%), in early or late first relapse (up to 60%), and in second or later relapse, where complete response rates decrease dramatically (as low as 10% with high-intensity regimens). Post-refractory OS has been reported at 5 months, with an EFS of 4.7 months. For patients in first relapse, the reported studies range from 5.8 months for those receiving salvage chemotherapy alone, increasing to 10 months if they undergo hematopoietic progenitor cell transplantation. For second relapses or relapses after transplantation, OS does not exceed 5 months. For patients who do not receive any treatment, the prognosis is grim, with high mortality within the following months following refractoriness or relapse without any support. 30,31,32
Therefore, it is proposed to increase the complete response rate with a pediatric-inspired chemotherapy regimen in conjunction with a BCL-2 inhibitor, so that patients can be transitioned to allogeneic bone marrow transplantation (the only curative therapy in this context), either after the treatment received or with short-term immunotherapy bridging to transplantation.
The risks associated with conventional salvage chemotherapy for patients with good performance status will not differ significantly from those typically observed in daily clinical practice (see below for the expected description of adverse events), since the basis of therapy remains the TACL regimen. A higher degree of cytopenias, especially neutropenia and thrombocytopenia, can be expected with the addition of a BCL-2 inhibitor.
Salvage chemotherapy will be assigned as follows:
- Venetoclax 100 mg orally every day for 7 days
- Itraconazole 100 mg orally every 12 hours for 7 days
- Vincristine 1.4 mg/m2 intravenously on days 1, 8, 15, and 22
- Mitoxantrone 6 mg/m2 intravenously on day 1
- L-Asparaginase 6,000 IU/m2 intramuscularly on days 5, 7, 9, 11, 13, 16, 18, 20, and 23
- Dexamethasone 20 mg orally from days 1 to 15
- Bortezomib 2 mg subcutaneously on days 1, 4, 8, and 11
- Rituximab 375 mg/m2 intravenously on day 8 for patients with CD20+, more than 20% expression in flow cytometry
- Intrathecal Chemotherapy or CNS (-): Days 8 and 15 or CNS (+): Days 1, 8, 15, and 22
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
- 16 Years 至 45 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •B-cell or T-cell acute lymphoblastic leukemia.
- •Philadelphia chromosome negative
- •Relapsed disease after any line of treatment, defined as detection of disease activity at any time after remission
- •Refractory disease after first-line treatment, defined as: more than 5% blasts after completion of induction/consolidation by flow cytometry
- •Not having included venetoclax in any prior regimen.
- •No prior organ damage, defined as the absence of any serious, life-threatening disease prior to the start of treatment.
- •Performance status defined by the ECOG scale between 0 and 2.
排除标准
- •Isolated CNS relapse.
- •Performance status defined by ECOG scale between 3 and
- •CTCAE-classified sensory or motor neuropathy of grade 3 or higher.
- •History of hypersensitivity or intolerance to the drugs included in the regimen.
- •Prior organ damage, defined as the presence of any serious, life-threatening illness prior to the start of treatment.
研究组 & 干预措施
TACL plus low dose Venetoclax and Itraconazole
Salvage chemotherapy will be assigned as follows:
- Venetoclax 100 mg orally every day for 7 days
- Itraconazole 100 mg orally every 12 hours for 7 days
- Vincristine 1.4 mg/m2 intravenously on days 1, 8, 15, and 22
- Mitoxantrone 6 mg/m2 intravenously on day 1
- L-Asparaginase 6,000 IU/m2 intramuscularly on days 5, 7, 9, 11, 13, 16, 18, 20, and 23
- Dexamethasone 16 mg orally from days 1 to 15
- Bortezomib 2 mg subcutaneously on days 1, 4, 8, and 11
- Rituximab 375 mg/m2 intravenously on day 8 for patients with CD20+, more than 20% expression
- Intrathecal Chemotherapy or CNS (-): Days 8 and 15 or CNS (+): Days 1, 8, 15, and 22
干预措施: Venetoclax low dose with itraconazole (Drug)
结局指标
主要结局
Overall response rata after low dose venetoclax with itraconazole plus TACL
时间窗: 16 months
To evaluate the overall response after reinduction to remission with low dose venetoclax plus TACL in patients with relapsed/refractory acute lymphoblastic leukemia
次要结局
- Adverse events evaluatio(16 months)
- Patients recieving HSCT after chemotherapy(24 months)
- Event-free survival(24 months)
- Overall survival(24 months)
- Percentage of measurable residual disease in complete response(16 months)
研究者
David Gomez Almaguer
Head of Hematology
Hospital Universitario Dr. Jose E. Gonzalez