Improving Treatment Outcomes in Chronic Myeloid Leukaemia Patients Using Imatinib and Artesunate Combination Therapy
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 75
- 试验地点
- 1
- 主要终点
- Major molecular remission
研究概览
简要总结
Chronic myeloid leukaemia (CML) is a blood cancer with an annual worldwide incidence of 1/100,000 population. Imatinib is used for the treatment of CML and has significantly improved the management of the disease. However, the incidence of treatment failure due to imatinib resistance has become a considerable burden (Sherbenou et al., 2007). Artesunate, an antimalarial drug, is reported to have anti-neoplastic effect either singly or in synergy with already established anti-neoplastic agents (Krishna et al., 2015).
The aim of the study is to evaluate the clinical effectiveness of an Imatinib-artesunate combination compared to imatinib alone and its possibility as an alternative option in the management of sub-optimal response in CML patients especially in low- and middle- income country like Nigeria where second line tyrosine kinase inhibitor may be out of reach.
The specific objectives are to:
- Assess the safety of artesunate use beyond its traditional antimalarial dosing period in CML patients.
- Compare treatment outcomes between patients on imatinib alone and patients on imatinib plus artesunate at 3, 6 and 12-months of follow-up.
- Determine the effect of imatinib and artesunate combination on the achievement of major molecular remission in CML patients with sub-optimal response to imatinib.
- Determine the effect of artesunate on imatinib pharmacokinetics following co-administration of the two drugs.
The main questions it aims to answer is:
- Does the use of artesunate in combination with imatinib in newly diagnosed CML patient give a better therapeutic outcome than using imatinib alone?
- Does combining artesunate with imatinib in CML patients with sub-optimal response to imatinib improve patients' response to imatinib?
- Does combining artesunate with imatinib in CML patients affect the pharmacokinetic parameter of imatinib?
- Is it safe to take artesunate at 4mg/day (not exceeding 200mg/day) for a 14day cycle in CML patients as demonstrated in other forms of cancer?
Participants will be assigned to one of the groups of the study and continue imatinib medication irrespective of the group assigned and come to clinic once a month for follow-up. Clinic visits will be immediately after a cycle of artesunate for groups B and C.
详细描述
Improving treatment outcomes in chronic myeloid leukaemia patients using Imatinib and Artesunate combination therapy.
Statement of Research Problem:
Imatinib is a first-line tyrosine kinase inhibitor (TKI) in the management of CML patients. At present, over one thousand Nigerians with CML are accessing free imatinib on the Glivec International Patient Assistance Program (GIPAP) platform at the Obafemi Awolowo University Teaching Hospital (OAUTH), Ile-Ife, Nigeria. This is the one of the two centres providing this service in the country and has been providing this service since 2003. However, only 40% of the patients had optimal clinical response while the rest had suboptimal response or treatment failure (Oyekunle et al., 2015). The high cost of alternative TKIs and/or stem cell transplantation hugely limits the treatment options available for Nigerian CML patients. Therefore, there is a strong need for an alternative therapeutic option that could optimize the management and clinical outcomes of CML in Nigeria and other resource-challenged countries.
Conceptual Framework of the Study:
This study explores drug repurposing for artesunate by investigating its anti-neoplastic effect in CML patients. Artesunate is a first-line antimalarial that has also demonstrated anti-leukemic activity in cell lines and murine models. Artesunate will be combined with imatinib and the synergy will be explored based on the multi-dimensional synergy of combination theory as described by Wooten (Wooten et al., 2019). The focus will be to evaluate the synergistic potency and synergistic efficacy of the combination. Synergistic potency is the amount of the change in drug potency, owing to the presence of another drug while synergistic efficacy is the percentage change in the maximal efficacy of the combination compared to the most efficacious single agent (Wooten et al., 2019). In this study, we will evaluate the pharmacokinetic interaction between artesunate and imatinib, and also determine the safety and efficacy of the combination, and the corresponding positive clinical outcomes in suboptimal CML patients. This approach has the potential to accelerate the translatability and reproducibility of this drug-synergy study by bridging the gap between the positive clinical outcome potential of the drug combination and the complexity of the study design.
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
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed chronic phase CML patients
- •Patients with sub-optimal response to imatinib therapy
- •Ages between 18 years and 85 years with written informed consent
排除标准
- •Patients with documented hypersensitivity to artesunate
- •Patients with cardiovascular disease, pregnancy and inability to give consent will be excluded.
- •Patients currently on any medication(s) that may interact with imatinib or affect its pharmacokinetics parameters (like rifampicin and ketoconazole) will be excluded.
研究组 & 干预措施
Group A: Imatinib alone in newly diagnosed CML patients
Imatinib (Glivec) at a dose of 400mg to newly diagnosed CML patients
干预措施: Imatinib (Drug)
Group B: Imatinib and artesunate combination therapy
Imatinib (Glivec) at a dose of 400mg daily and artesunate at a dose of 4mg/kg (not exceeding 200mg) daily in newly diagnosed CML patients
干预措施: Imatinib (Drug)
Group B: Imatinib and artesunate combination therapy
Imatinib (Glivec) at a dose of 400mg daily and artesunate at a dose of 4mg/kg (not exceeding 200mg) daily in newly diagnosed CML patients
干预措施: Artesunate (Drug)
Group C: Imatinib and artesunate in CML patients
Imatinib (Glivec) 400mg and artesunate 400mg in CML patients with documented sub-optimal response to Imatinib, patients will be monitored monthly and reviewed after 3 months
干预措施: Imatinib (Drug)
Group C: Imatinib and artesunate in CML patients
Imatinib (Glivec) 400mg and artesunate 400mg in CML patients with documented sub-optimal response to Imatinib, patients will be monitored monthly and reviewed after 3 months
干预措施: Artesunate (Drug)
结局指标
主要结局
Major molecular remission
时间窗: 12 months
The primary endpoint will be the achievement of Major Molecular remission (MMR/MR3) with bcr/abl-1 gene transcript ≤0.1 and deep molecular response (MR4) with bcr/abl-1 gene transcript ≤0.01 at 12 months.
次要结局
- Plasma Imatinib levels(3 months, 6 months and 12 months)
- Disease progression(3 months, 6 months, 12 months)
- Adverse events relating to long-term use of artesunate(Accessed after each cycle every month through the 12 months follow-up)
研究者
Famurewa Oluwatoyin
Mrs.
Obafemi Awolowo University