A Phase Ib Study of the Combination of Venetoclax With Chemotherapy as Frontline Therapy in Older Patients and Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 82
- 试验地点
- 10
- 主要终点
- Maximum Tolerated Dose
研究概览
简要总结
This research study is studying a medication called Venetoclax and a chemotherapy regimen as a possible treatment for Acute Lymphoblastic Leukemia.
The drugs involved in this study are:
- Venetoclax
- Standard Chemotherapy (which includes cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, 6-mercaptopurine, etoposide, and cytarabine
详细描述
This research study is a Phase I clinical trial, which tests the safety of an investigational drug and drug combination and also tries to define the appropriate dose of the investigational drug and drug combination to use for further studies. "Investigational" means that the drug and drug combination is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved Venetoclax for this specific disease, but it has been approved for other uses.
Venetoclax is an inhibitor of Bcl-2. Bcl-2 is critical for keeping cancer cells alive.
By inhibiting Bcl-2, venetoclax promotes cancer cell death. This drug is currently being used in other clinical trials for people with certain types of leukemia, lymphoma, and multiple myeloma. There is some evidence from those and other laboratory trials that venetoclax may kill cancer cells and cause tumors to shrink.
In this research study, the investigators are investigating how safe the combination of Venetoclax and standard chemotherapy is and how it affects this disease.. The participant will be given Venetoclax alone first and the standard chemotherapies will be given in combination. This study aims to provide information to help determine the dose of Venetoclax , in combination with standard chemotherapy, affects this disease the best and which dose is the safest.
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 previously untreated acute lymphoblastic leukemia (B-cell or T-cell)
- •Bone marrow involvement with ≥20% lymphoblasts
- •Age ≥ 60 Years
- •Patients with relapsed or refractory acute lymphoblastic leukemia (B-cell or T-cell) defined as receiving one or more cytotoxic containing regimens
- •Bone marrow involvement with ≥5% lymphoblasts
- •Age ≥ 18 Years
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Refer to Appendix D)
- •Adequate organ function
- •Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert's disease
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, unless clearly due to disease involvement
- •Creatinine clearance >50 mL/min (calculated according to institutional standards or using Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formula)
- •Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug. Women of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
- •Patients or their legally authorized representative must provide written informed consent
排除标准
- •Ph-positive ALL, Burkitt's leukemia/lymphoma, or lymphoblastic lymphoma
- •Patient is pregnant or breastfeeding
- •Patients with uncontrolled infection
- •Hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)
- •Major surgery or radiation therapy within 4 weeks prior to the first study dose
- •Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and/or dexamethasone, or one dose of cytarabine) prior to starting therapy
- •Symptomatic or untreated leptomeningeal disease or spinal cord compression
- •Patients with active heart disease (New York Heart Association (NYHA) class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months)
- •Patients with a cardiac ejection fraction (as measured by either Multi Gated Acquisition (MUGA) or echocardiogram (EKG)) <40%
- •History of another primary invasive malignancy that has not been definitively treated or in remission for at least 2 years. Patients with non-melanoma skin cancers or with carcinomas in situ are eligible regardless of the time from diagnosis (including concomitant diagnoses)
- •Concurrent use of warfarin
- •Received Cytochrome P450 3A (CYP3A) inhibitors (such as fluconazole, ketoconazole, voriconazole, and clarithromycin) within 3 days of starting venetoclax; received strong CYP3A inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St. John's Wort) within 3 days of starting venetoclax
- •Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days prior to starting venetoclax
- •Prior treatment with venetoclax
- •Malabsorption syndrome or other conditions that preclude enteral route of administration
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
研究组 & 干预措施
Venetoclax + Chemotherapy
- Venetoclax is administered orally once daily for 21 days in each cycle
- Standard Chemotherapy will be administered every 28 days
干预措施: Standard Chemotherapy (Drug)
Venetoclax + Chemotherapy
- Venetoclax is administered orally once daily for 21 days in each cycle
- Standard Chemotherapy will be administered every 28 days
干预措施: Venetoclax (Drug)
结局指标
主要结局
Maximum Tolerated Dose
时间窗: 2 years
To determine the maximum tolerated dose (MTD) of venetoclax in combination with chemotherapy in patients with newly diagnosed Acute Lymphoblastic Leukemia (ALL)
次要结局
- To Evaluate The Safety of the Combination(2 years)
- Complete Response(2 years)
- Progression Free Survival(2 years)
- Overall Survival(2 years)
- Minimal Residual Disease(2 years)
- Disease Free Survival(2 years)
- Change in expression of BCL-2 family proteins: BCL-2(2 years)
- Change in expression of BCL-2 family proteins: BCL-XL(2 years)
- Change in expression of BCL-2 family proteins: MCL-1 (anti-apoptotic)(2 years)
- Change in expression of BCL-2 family proteins: BCL-2 homology 3 (BH3)(2 years)
- Change in expression of BCL-2 family proteins: BIM(2 years)
- Change in expression of BCL-2 family proteins: BID(2 years)
- Change in expression of BCL-2 family proteins: BAD(2 years)
- Change in expression of BCL-2 family proteins: NOXA(2 years)
- Change in expression of BCL-2 family proteins: PUMA(2 years)
- Change in expression of BCL-2 family proteins: HRK (pro-apoptotic)(2 years)
研究者
Marlise Luskin, MD
Principal Investigator
Dana-Farber Cancer Institute