A Phase 1/2 Study of SNDX-275 in Combination With Imatinib for Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Entinostat When Given in Combination With Imatinib Mesylate
研究概览
简要总结
This phase I/II trial is studying the side effects and best dose of entinostat when given together with imatinib mesylate and to see how well it works in treating patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Entinostat and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth
详细描述
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of entinostat when given in combination with imatinib (matinib mesylate).
SECONDARY OBJECTIVES:
I. To estimate the rate of complete response (CR) for patients greater ≥ 18 years of age with relapsed/refractory Ph+ ALL treated with a combination of entinostat and imatinib.
II. To estimate the 1 year progression free survival (PFS) for patients greater ≥ 18 years of age with relapsed/refractory Ph+ ALL treated with a combination of entinostat and imatinib III. To describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of entinostat when administered alone vs. in combination with imatinib.
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
- •Patients must have histologically confirmed BCR-ABL1 associated (Ph+) acute lymphoblastic leukemia (ALL) with primary refractory or relapsed disease; demonstration of BCR-ABL1 in leukemia cells by one or more of the following is required: t(9;22)(q34;q11.2) cytogenetics; FISH for BCR-ABL1 fusion; RT-PCR for BCR-ABL1 fusion
- •Prior treatment with tyrosine kinase inhibitors (including imatinib, nilotinib and/or dasatinib) is allowed, although patients must be off any tyrosine kinase inhibitor for a minimum of 72 hours prior to beginning protocol therapy
- •ECOG performance status of 0, 1 or 2
- •Total WBC =< 150,000 with no evidence for ongoing or impending leukostasis
- •Total bilirubin =< 2.0 mg/dL unless elevated due to Gilbert's, hemolysis or leukemic infiltration
- •Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 × upper limit of normal (ULN) unless due to leukemic infiltration
- •Serum creatinine =< 2.0 mg/dL or creatinine clearance > 50 ml/min
- •Left ventricular ejection fraction (LVEF) >= 45% as measured by echocardiogram (ECHO) or MUGA
- •Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are > 4 weeks from stem cell infusion, have no active GVHD, and meet other eligibility criteria
- •Patients who fail primary induction therapy or relapse after achieving complete remission (CR) are eligible if they are > 3 weeks off cytotoxic chemotherapy and > 2 weeks off radiation therapy; patients must be off biologic therapies including hematopoietic growth factors > 1 week; if using hydroxyurea (HU), steroids, or other non-cytotoxics for blast count control, patient must be off for > 24 hrs before starting protocol therapy; patients must have recovered from all acute toxicities from any previous therapy
- •Female patients of childbearing age must have negative pregnancy test; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Patients may not be receiving any other investigational agents
- •Active CNS leukemia; patients with known previous CNS leukemia may continue to receive intrathecal therapy with ara-C, methotrexate, and/or thiotepa plus steroids as prophylaxis against reactivation of previous CNS disease
- •Patients may not have received previous treatment with entinostat or other HDAC inhibitors
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to entinostat or other agents used in study
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active untreated infection, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with entinostat
- •HIV-positive patients on combination antiretroviral therapy are ineligible
研究组 & 干预措施
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: entinostat (Drug)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: imatinib mesylate (Drug)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: western blotting (Genetic)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: immunohistochemistry staining method (Other)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: flow cytometry (Other)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: polymerase chain reaction (Genetic)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: high performance liquid chromatography (Other)
Treatment (entinostat and imatinib mesylate)
Patients receive entinostat PO daily on days 1, 8, 15, and 22 and imatinib mesylate PO twice daily on days 1-28 (days 4-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: mass spectrometry (Other)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Entinostat When Given in Combination With Imatinib Mesylate
时间窗: Up to 30 days post-treatment
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.
次要结局
- Progression Free Survival (PFS) for Adults With Relapsed/Refractory Ph+ ALL Treated With Combination of Entinostat and Imatinib Mesylate(At 1 year)
- Rate of Complete Response (CR) for Adults With Relapsed/Refractory Ph+ ALL Treated With a Combination of Entinostat (at the Dose Determined in Phase 1) and Imatinib Mesylate(Up to 30 days post-treatment)
- Comparative Pharmacokinetics (PK) and Pharmacodynamics (PD) of Entinostat Alone vs. Entinostat Plus Imatinib Mesylate(Day 4 and 11)
- Predictive Values of Levels of Flow Cytometric Minimal Residual Disease (MRD) on Duration of Progression Free Survival for the Study Population(Day 29)