A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine. (Omacetaxine) (CGX-635) in the Treatment of Patients With Chronic Myeloid Leukemia. (CML) With the T315I BCR-ABL Gene Mutation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 103
- 试验地点
- 32
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total
研究概览
简要总结
To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain gene mutation.
详细描述
Point mutations within the ABL kinase domain of the BCR-ABL gene are emerging as the most frequent mechanism for resistance to imatinib and resultant reactivation of kinase activity. The risk of mutation development is particularly high in patients who are beyond chronic phase, as well as those with a long duration of disease prior to imatinib therapy.
The T315I kinase domain (KD) point mutation has merited particular attention, as T315I expressing CML cells are markedly resistant to imatinib. CML patients with the T315I KD mutation, therefore, do not respond to continued treatment with imatinib, and preliminary clinical data indicate that neither of two newer tyrosine kinase inhibitors will have activity in patients with T315I KD mutation either.
Omacetaxine mepesuccinate (HHT) is a potent inducer of apoptosis (programmed cell death) in myeloid cells and inhibits angiogenesis (blood vessel formation). In Phase 2 studies, HHT has demonstrated clinical activity in patients with CML, both as a single agent and in-combination with other chemotherapeutic drugs. HHT works via a different mechanism than imatinib or other tyrosine kinase inhibitors (TKI's), and HHT has been shown to inhibit in vitro CML cell lines which harbor the T315I KD mutation and are highly resistant to imatinib. Therefore, CML patients who have the T315I KD mutation may still respond to treatment with HHT. HHT may therefore be an attractive therapeutic option for patients with the T315I KD mutation.
On this basis, a multicenter clinical trial is being conducted of HHT therapy for CML patients who have failed prior imatinib therapy and have the T315I KD mutation.
Patients will be treated with an induction course consisting of subcutaneous (SC) HHT twice daily for 14 consecutive days every 28 days. Patients who demonstrate a response, may receive maintenance therapy for up to 24 months, consisting of subcutaneous (SC) HHT twice daily for 7 days every 28 days.
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, age 18 years or older
- •Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase
- •The patient will have the T315I BCR-ABL gene mutation
- •Patients will have failed prior imatinib therapy
- •ECOG performance status 0-2
排除标准
- •NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure
- •Myocardial infarction in the previous 12 weeks
- •Lymphoid Ph+ blast crisis
研究组 & 干预措施
omacetaxine
Treatment was the same for all cohorts: induction therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m^2 twice a day (BID), administered for 14 consecutive days every 28 (±3) days for up to 6 cycles. Maintenance therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m^2 twice a day (BID), administered for 7 consecutive days every 28 (±3) days for up to 3 years.
干预措施: Omacetaxine mepesuccinate (Drug)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total
时间窗: up to 3 years
TEAE are any untoward events that were newly occurring or worsening from Baseline. Treatment related toxicity was considered by the investigator to be unrelated, possibly, probably or unknown related to study drug. Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death. A serious adverse event (SAE) is any untoward medical occurrence that is fatal or life-threatening; results in persistent or significant disability or incapacity; requires or prolongs in-patient hospitalization; is a congenital anomaly/birth defect in the offspring of a patient; and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above. A participant is only counted once in each category (at worst severity or strongest relationship).
Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population
时间窗: Day 1 up to 6 months
Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses. Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful. Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available. Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows \>0% - 35% Ph+ cells. Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.
Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population
时间窗: Day 1 up to 6 months
Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses. Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last \>= 8 weeks to be considered meaningful. Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.
次要结局
- Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+)(Day 1 up to Month 9)
- Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response(Day 1 up to Month 6)
- Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response(up to 3 years)
- Kaplan-Meier Estimates for Duration of Best Cytogenetic Response(up to 4 years)
- Percentage of Participants in Each Hematologic Response Category(Day 1 up to Month 6)
- Kaplan-Meier Estimates for Duration of Best Hematologic Response(up to 4 years)
- Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS(Day 1 up to Month 6)
- Percentage of Participants With Extramedullary Disease (EMD) at Baseline Achieving a Clinical Response(Day 1 up to Month 9)
- Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL(Day 1 up to Month 6)
- Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL(Day 1 up to Month 9)
- Number of Treatment Cycles Needed to Achieve Best Hematologic Response(Day 1 up to Month 6)
- Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response(Day 1 up to 22 months)
- Kaplan-Meier Estimates for Overall Survival(up to 4 years)
- Kaplan-Meier Estimates for Time to Disease Progression(up to 4 years)