A Combination of PKC412 and 5-Azacytidine for the Treatment of Patients With Refractory or Relapsed Acute Leukemia and Myelodysplastic Syndrome (MDS)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Overall Response (OR) Within 6 Months
研究概览
简要总结
The goal of this clinical research study is to learn if the combination of PKC412 (also called Midostaurin) and 5-azacytidine can help to control refractory or relapsed acute leukemia and MDS. The safety and best dose of the combination of the drugs will also be studied.
详细描述
The Study Drugs:
PKC412 is designed to block certain receptors (FLT3-Kinase) on cancer cells that are responsible for cancer growth. This may cause the cancer cells to die.
5-azacytidine is designed to cause changes to certain genes that are thought to participate in causing leukemia. These changes are thought to silence these genes so they cannot contribute any longer to sustain the growth of leukemia and MDS.
Study Groups:
If you are found to be eligible to take part in this study, you will be assigned to a part of the study based on when you join.
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 with MDS, chronic myelomonocytic leukemia (CMML), AML or biphenotypic or bilineage leukemia who have failed prior therapy. Patients with MDS or CMML should have failed prior therapy with a hypomethylating agent and/or with lenalidomide. Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy, or be previously untreated and unable or unwilling to receive conventional chemotherapy (e.g., patients age >/=65 years). Patients with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The World Health Organization (WHO) classification will be used for AML. Patients with MDS, CMML or AML who have received no prior therapy are eligible if not candidates to receive or refuse standard therapy.
- •Patients must have evidence of FLT3 activating mutations.
- •Age >/= 18 years
- •Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2
- •Adequate liver (bilirubin </= 2x ULN, alanine aminotransferase (ALT) </= 2.5x ULN) and renal (creatinine </= 2x ULN) function
- •Patients must provide written informed consent.
- •Patients must have been off chemotherapy for 2 weeks prior to entering this study, unless there is evidence of rapidly progressive disease, and must have recovered from the toxic effects of that therapy to at least grade
- •Use of hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and for the first four weeks on therapy.
- •Women of childbearing potential must practice contraception. Women considered not of childbearing potential include any of the following: no menses for at least 5 years or menses within 5 years but amenorrheic for at least 2 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal range (according to definition of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and amenorrheic for at least 3 months. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation.
- •**continued from above: Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study.
- •Sexually active males should use a condom during intercourse while taking drug and for 3 months after stopping midostaurin medication. They should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid .
- •Negative urine or serum pregnancy test within 2 weeks.
排除标准
- •Patients with known allergy or hypersensitivity to PKC412, mannitol or 5-azacytidine, or any of their components.
- •Patients who have received any treatment of midostaurin prior to study entry.
- •Patients with known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC
- •Patients who demonstrated primary resistance to any FLT3 inhibitor or who relapsed while on therapy with a FLT3 inhibitor.
- •Patients with any other known disease (except carcinoma in-situ) concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes with fasting glucose > 200 mg/dl despite optimal management, cardiovascular disease including congestive heart failure (NYHA Class III or IV), myocardial infarction within 6 months and poorly controlled hypertension with systolic > 160 mmHg and diastolic > 100 mmHg, chronic renal disease, or active uncontrolled systemic infection) which could compromise participation in the study.
- •Patients with a known confirmed diagnosis of HIV infection or active viral hepatitis. HIV patients not on specific antiretroviral therapy are eligible for participation.
- •Patients who have had any major surgical procedure within 14 days of Day
- •Patients unwilling or unable to comply with the protocol.
- •Patients with known advanced malignant disease of the central nervous system.
- •Impaired cardiac function including any of the following: Screening ECG with a corrected QT interval (QTc) > 470 msec; Patients with congenital long QT syndrome; History or presence of sustained ventricular tachycardia; Any history of ventricular fibrillation or torsades de pointes; Bradycardia defined as Heart Rate (HR) < 50 bpm; Right bundle branch block + left anterior hemiblock (bifascicular block); Patients with myocardial infarction or unstable angina < 6 months prior to starting study drug; congestive heart failure (CHF) NY Heart Association class III or IV; Patients with an ejection fraction < 50% assessed by multigated radionuclide angiography (MUGA) or echocardiogram (ECHO) scan within 14 days of Day 1.
研究组 & 干预措施
5-azacytidine + PKC412
5-azacytidine 75 mg/m2/d subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 50 mg by mouth twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).
干预措施: 5-azacytidine (Drug)
5-azacytidine + PKC412
5-azacytidine 75 mg/m2/d subcutaneously (SQ) or by vein (IV) on days 1-7 of a 28 day cycle. PKC412 50 mg by mouth twice daily for 14 days (days 8-21), of every 28 day cycle. Starting with cycle 2, PKC412 administered continuously (daily).
干预措施: PKC412 (Drug)
结局指标
主要结局
Overall Response (OR) Within 6 Months
时间窗: 6 Months
Overall response defined as number of participants with response as follows: (OR = CR \[complete response (CR) rate\] + CRi \[complete remission with incomplete count recovery\] + PR \[partial remission\] + HI \[hematologic improvement\]) within 6 months of treatment initiation. complete remission (CR), a CR with incomplete bone marrow recovery (CRi), a morphologic leukemia-free status (MLFS), or a partial remission (PR). CR: \<5% bone marrow blasts, neutrophil count\>1.0 X10⁹/L, \& platelet count\>100 X10⁹/L. CRi: all CR criteria except residual neutropenia (\<1.0 X10⁹/L) or thrombocytopenia (\<100 X10⁹/L). MLFS: \<5% blasts in bone marrow regardless of neutrophil \& platelet count in peripheral blood. PR: all CR criteria, except reduction\> 50% in bone marrow blasts, but still \>5%.
Participant Best Response Assessed Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
时间窗: 6 months
Criteria for response per international working group for Myelodysplastic Syndrome (MDS) \& acute myeloid leukemia (AML) where responders obtained a complete remission (CR), a CR with incomplete bone marrow recovery (CRi), a morphologic leukemia-free status (MLFS), or a partial remission (PR). CR: \<5% bone marrow blasts, neutrophil count\>1.0 X10⁹/L, \& platelet count\>100 X10⁹/L. CRi: all CR criteria except residual neutropenia (\<1.0 X10⁹/L) or thrombocytopenia (\<100 X10⁹/L). MLFS: \<5% blasts in bone marrow regardless of neutrophil \& platelet count in peripheral blood. PR: all CR criteria, except reduction\> 50% in bone marrow blasts, but still \>5%. Clinical responses evaluated using RECIST version 1.1 criteria after every two cycles, with confirmation of clinical response at 4 weeks after achieving response.
次要结局
未报告次要终点