A Phase Ib Study of Belinostat With RDHAP Chemotherapy (Dexamethasone, Cytarabine, Cisplatinum) in Adults With Relapsed or Refractory Diffuse Large B-cell Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Maximum Tolerated Dose (MTD) of Belinostat with RDHAP Chemotherapy in Participants with Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
研究概览
简要总结
The goal of this clinical research study is to find the highest tolerable dose of belinostat that can be combined with standard chemotherapy drugs (rituximab, cisplatin, cytarabine, and dexamethasone) in patients with relapsed or refractory DLBCL who are eligible for an autologous stem cell transplant (a transplant of the patient's own stem cells). The safety of the study drug will also be studied.
详细描述
Study Groups:
If participant is found to be eligible to take part in this study, they will be assigned to a dose level of belinostat based on when they join this study. Up to 4 dose levels of belinostat will be tested. Between 3-6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of belinostat is found.
All participants will receive the same dose level of the standard chemotherapy drugs.
Study Drug Administration:
Participant will receive belinostat with standard chemotherapy for up to two 21-day cycles.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aggressive B-cell lymphoma, including DLBCL and FL or other indolent or low grade malignancy transforming to DLBCL, Grade III FL, Burkitt lymphoma, and unclassifiable B-cell lymphoma with features of Burkitt and DLBCL according to the World Health Organization, with biopsy confirmation of disease which has relapsed after or refractory to a standard cytotoxic chemotherapy combination including rituximab and doxorubicin, for whom an autologous stem cell transplant is planned.
- •Have received between 1 - 2 prior cytotoxic treatments, not to include belinostat, RDHAP, or autologous or allogeneic stem cell transplant. Radiation which was pre-planned to occur at the conclusion of systemic cytotoxic therapy will not be considered a separate prior therapy. Radiation administered for potential recurrent or relapsed disease will be considered a separate prior therapy.
- •Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an IRB-approved informed consent form.
- •Age 18-80 years at the time of signing the informed consent.
- •Patients must have bi-dimensional measurable disease.
- •Patients with performance status of </=3 (Eastern Cooperative Oncology Group Performance Status Scale, 3 only allowed if decline in status is deemed related to lymphoma and felt potentially reversible by the treating physician).
- •Within 4 weeks of therapy start, serum bilirubin <1.5x ULN (maximum level based on MD Anderson laboratory ranges is 1.95 mg/dL); AST (SGOT) and ALT (SGPT) </=3x ULN or < 5x ULN if hepatic metastases are present; ANC >1000/mm^3 and platelets >100,000/mm^3 unless deemed likely related to lymphoma involvement in the bone marrow where the minimum ANC allowable will be 500/mm^3 and minimum allowable platelet count will be 50,000/mm^
- •Within 4 weeks of therapy start, renal function assessed by calculated creatinine clearance >/= 50ml/min by Cockcroft-Gault formula using actual body weight.
- •Patients must be willing to receive transfusions of blood products.
- •Within 4 weeks of therapy start, women of childbearing potential must have a negative serum (Beta-human chorionic gonadotropin [Beta-hCG]) or urine pregnancy test at screening and must adhere to the scheduled pregnancy testing.
- •Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of birth control during and after the study (12 months for women and 3 months for men), consistent with local regulations regarding the use of birth control methods for subjects participating in this clinical study.
排除标准
- •Any serious medical condition including but not limited to uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, COPD, left ventricular ejection fraction of less than 40, active infection, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form. Patients with history of cardiac arrhythmias should have cardiac evaluation and clearance.
- •Pregnant or lactating females.
- •Known hypersensitivity to any component of RDHAP.
- •Patients with Gilbert's syndrome unless homozygosity for the UFT1A1*28 mutation has been excluded.
- •HIV infection, active hepatitis B infection, active hepatitis C infection.
- •Known homozygous for UGT1A1*28 mutation from prior testing or family history.
- •Requirement of therapy with a UGT1A1 Inhibitor, as detailed in Section 8.4, or use within 7 days of enrollment on this protocol.
- •All patients with active central nervous system involvement with lymphoma.
- •Diagnosis of prior malignancy within the past 2 years with the exception of successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast. History of other malignancies are allowed if in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years.
- •Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment.
研究组 & 干预措施
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Fluconazole (Drug)
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Belinostat (Drug)
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Rituximab (Drug)
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Cisplatin (Drug)
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Cytarabine (Drug)
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Dexamethasone (Drug)
Belinostat + RDHAP Chemotherapy
Belinostat administered by vein on Days 1 - 2 of a 21-day cycle. Rituximab administered by vein on Day 2. Cisplatinum administered by vein on Day 2. Cytarabine administered by vein on Day 3 during the initial cohorts, and on Day 2 in the cohort of modified DHAP scheduling. Ciprofloxacin 500 mg twice daily for 10 days and Fluconazole 100 mg daily for 10 days may be utilized at the discretion of the treating physician.
干预措施: Ciprofloxacin (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Belinostat with RDHAP Chemotherapy in Participants with Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
时间窗: 21 days
MTD defined as the highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). DLT defined as an adverse event at least possibly related to study treatment: 1. Any grade 3 or higher non-hematological toxicity possibly related to study medications per National Cancer Institute Common Terminology Criteria for Adverse Events v4.0, with exclusion of grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours 2. Any non-hematological toxicity requiring a delay of next cycle of therapy for greater than 14 days; 3. Grade 4 neutropenia which persists for 14 or greater days despite growth factor support. 4. Neutropenic fever incidence closely monitored, but will not be considered a DLT due to known high rate of neutropenic fever with dose adjusted RDHAP (20 - 30%).
次要结局
- Overall response Rate (ORR)(1 year)