Phase 2 Clinical Trial With Ponatinib as a Second Line Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Prior First Line Tyrosine Kinase Inhibitor Treatment
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- GWT-TUD GmbH
- 入组人数
- 18
- 试验地点
- 10
- 主要终点
- Major Molecular Response (MMR) of treatment
研究概览
简要总结
This study will include patients suffering from chronic myeloid leukemia (CP-CML), who were treated with tyrosine kinase inhibitor (TKI, a substance that blocks the action of enzymes) in a previous therapy but which has not been effective. Patients will be treated with Ponatinib 30 mg in in this study. The aim of the study is to evaluate the safety and efficacy of Ponatinib as a second line treatment in patients failing or not tolerating first line therapy with any other approved TKIs. It is expected that Ponatinib, due to its efficacy, may be more effective as second line therapy than other approved TKIs and lead to improved overall survival. The effect will be determined by the molecular response rate (MMR) as the primary objective after 12 months of treatment. The safety of the drug will be evaluated on the basis if routine medical and laboratory examinations.
详细描述
Despite significant progress in the treatment of patients with chronic phase CML, there is still need to further optimize therapy to reach the goal of disease eradication for almost all patients. In case of imatinib failure, dasatinib and nilotinib are effective treatment options after an individualized treatment selection. Although MMR rates of around 30% after 2 years of therapy are a significant achievement, options that may improve response rates in depth are still desirable. Ponatinib is a third generation TKI with very high anti-clonal activity in all CML phases. Moreover, it also eradicates most of the known and problematic mutations and only very few (compound) mutations may induce ponatinib-resistance.
Based on its favourable target spectrum, it is expected that Ponatinib may be more effective than 2nd line dasatinib or nilotinib in achieving early (i.e., at 6 months) cytogenetic and molecular responses in patients after inappropriate response to imatinib, and more effective as 2nd line treatment after failure of initial treatment with dasatinib or nilotinib than a cross-over between the 2nd generation TKIs. The basic hypothesis underlying therapeutic programs in CML is to be able to achieve meaningful and long-lasting suppression of the Philadelphia chromosome and breakpoint cluster region-abelson fusion gen (BCR-ABL). Complete cytogenetic responses have been associated with improved survival in CML, while major molecular responses are associated with improved event-free survival.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients ≥18 years old
- •Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML
- •Patients should have demonstrated to have
- •a failure of a prior 1st line TKI treatment with either imatinib, dasatinib or nilotinib. Failure is defined as per European LeukemiaNet (ELN) recommendations:
- •Less than Complete Hematologic Response (CHR) and/or Ph+ > 95% at or beyond 3 months
- •No cytogenetic response (Ph+>35%) and/or Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) >10% at or beyond 6 months
- •BCR-ABL (on international scale) >1% and/or PH+ >0%
- •Less than MMR at or beyond 18 months
- •Loss of response or development of mutations or other clonal chromosomal abnormalities at any time during the first line TKI treatment
- •or intolerance to prior TKI treatment defined as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management including dose adjustment, or in a patient where dose reductions are considered to be not in the patient's best interest to obtain an adequate response. Intolerant patients should not have achieved or have lost major molecular response at the time of enrollment
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
排除标准
- •Any 1st line anti-CML treatment other than TKI (apart from therapy with hydroxyurea)
- •Any 2nd line therapy with a tyrosine kinase inhibitor (>1 European Medicines Agency (EMA) approved TKI for CML, or any investigational non EMA-approved TKI)
- •Concurrent participation in any other clinical trial involving another investigational drug within 4 weeks prior to enrollment and throughout participation in PONS-Study
- •New York Heart Association (NYHA) cardiac class 3-4 heart disease
- •Cardiac Symptoms within the past 12 months prior recruitment
研究组 & 干预措施
Ponatinib
Patients in this treatment arm receive Ponatinib: starting dose 30 mg once-daily. Doses may be increased in case of inappropriate response and reduced to manage drug-related adverse events (AEs) and may be re-escalated once events resolve.
干预措施: Ponatinib (Drug)
结局指标
主要结局
Major Molecular Response (MMR) of treatment
时间窗: by 12 moths
To estimate the proportion of CP-CML patients with tyrosine kinase inhibitor (TKI)-resistance or intolerance to first line therapy with TKI, attaining MMR by 12 months of treatment with second line Ponatinib therapy.
次要结局
- Occurrence of BCR-ABL-mutations(at 3, 6, 9, 12, 18 and 24 months)
- Time to toxicity(up to 24 months)
- Time to progression(at 3, 6, 9, 12, 18 and 24 months)
- Time to response(at 3, 6, 9, 12, 18 and 24 months)
- Durations of response(at 3, 6, 9, 12, 18 and 24 month)
- Time to overall survival(at 3, 6, 9, 12, 18 and 24 month)