Phase I/II Study of the Combination of Bendamustine, Rituximab and Pixantrone in Patients With Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose
研究概览
简要总结
This is a phase I trial of the combination of bendamustine, rituximab and pixantrone in patients with relapsed/refractory B cell non-Hodgkin lymphoma. A standard 3+3 design will be used to determine the maximum tolerated dose (MTD) of the combination. A static dose of bendamustine and rituximab will be used and the dose of pixantrone will be escalated in each cohort. Pixantrone will be dosed on a 21 day cycle at 55mg/m2, 85mg/m2, and 115mg/m2 in sequential cohorts dependent on acceptable toxicity profile at each dose level. MTD will be determined based on DLTs that occur during the first 2 cycles of the drug combination.
Phase II did not proceed as planned due to withdrawal of pixantrone from the US.
详细描述
This is a phase I trial utilizing a traditional 3+3 design to evaluate maximum tolerated dose (MTD) and optimal dose schedule of pixantrone in combination with bendamustine (120mg/m2 on day 1 of each 21 day cycle) and rituximab (375mg/m2 on day 1 of each 21 day cycle). No patients will be entered on an escalated dosage level until at least 3 patients have been treated at the previous level and assessed for a dose limiting toxicity. Dose levels will be escalated in cohorts of 3 patients as long as no drug-related DLT occurs in the first 2 cycles. If one patient is observed to suffer a DLT, this cohort will be expanded to include at least 6 patients total. If less than 2 patients in the expanded cohort of 6 patients experience a DLT, dose escalation will resume. If 2 of 6 patients enrolled at the same dose level experience a DLT, the MTD has been exceeded, and the dose escalation will cease. The next lower dose will be considered the MTD. If any patient withdraws from the study prior to completing 2 cycles for reasons other than a DLT then that patient will be replaced in order to determine the MTD.
If dose limiting toxicity is observed at the initial dose level in 2 patients, the MTD has been exceeded and the starting dose level will be reduced to 25mg/m2. If 1 patient experiences a DLT in the -1 dose range, the cohort will be expanded to at least 6 patients. If a second patient experiences a DLT at the -1 dose level, the trial will be closed.
For part 1, those who have a confirmed diagnosis of relapsed/refractory B cell non-Hodgkin's lymphoma of any subtype will be considered eligible for enrollment. Each cycle will be 21 days. Subjects will be assessed for DLTs during the first 2 cycles of study drug. They will be assessed for response after cycle 2. Patients not experiencing a DLT during the first 2 cycles and who have stable disease or better may continue to receive up to 6 cycles of treatment with the triplet combination. If any patient withdraws from the study prior to completing 2 cycles for reasons other than a DLT then that patient will be replaced in order to determine the MTD.
Phase II did not proceed as planned due to withdrawal of pixantrone from the US.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Part I: Subjects must have relapsed or refractory B cell NHL;
- •Part II: Subjects must have relapsed or refractory aggressive B cell NHL including follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL), transformed NHL, mantle cell lymphoma (MCL), or other aggressive B cell NHL histology as per the WHO 2008 criteria;
- •Refractory disease (defined as persistence of evaluable disease after therapy) or relapsed disease following at least one prior treatment regimen that should include autologous stem cell transplant unless a patient was not eligible or refused prior transplant;
- •Age ≥ 18 years old;
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤2;
- •Subjects must have measurable or evaluable disease based on physical exam and/or radiographs (CT, MRI, PET) or bone marrow involvement;
- •Female subject is either post-menopausal or surgically sterilized;
- •Laboratory Values:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; lower levels accepted if due to marrow involvement by lymphoma
- •Platelets ≥ 75,000/mcl; lower levels accepted if due to marrow involvement by lymphoma
- •Total bilirubin ≤ 1.5 X institutional upper limit of normal; ≤ 3.0 ULN accepted in subjects with Gilbert's Syndrome
- •AST/ALT ≤ 1.5 X institutional upper limit of normal. Subjects with known liver involvement by lymphoma: AST/ALT ≤ 2 X institutional upper limit of normal
- •Serum creatinine < 1.5 X institutional upper limit of normal
- •Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
排除标准
- •No chemotherapy, radiation, biologics or immunotherapy within 2 weeks prior to registration (6 weeks if last received BCNU or mitomycin C).
- •No radioimmunotherapy within 2 months prior to registration.
- •Subjects receiving chronic, systemic treatment with corticosteroids equivalent to > 20mg of prednisone per day. Subjects receiving replacement for adrenal insufficiency will be allowed on the study. Topical or inhaled corticosteroids are allowed.
- •Subjects with a history of another primary malignancy ≤ 3 years ago, with the exception of inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a PSA that has not increased for at least 3 months, carcinoma in situ of the cervix.
- •Major surgery ≤ 4 weeks prior to registration. Minor surgery ≤ 2 weeks prior to registration. Insertion of a vascular access device is not considered major or minor surgery. Subjects must have recovered from all surgery related toxicities to ≤ grade 1 or to baseline if subject started with > grade 1 toxicity, not otherwise violating the above inclusion criteria.
- •Subjects who have received investigational drugs ≤ 4 weeks prior to registration.
- •Impaired Cardiac Function:
- •QTc > 480 on screening ECG.
- •Previous history of angina pectoris or acute MI within 6 months
- •Congestive heart failure (New York Heart Association functional classification III-IV) or baseline MUGA/ECHO shows estimated LVEF < 45%
- •Any history of torsade de pointes, ventricular fibrillation, uncontrolled ventricular tachycardia, or uncontrolled atrial fibrillation.
- •Female patients who are pregnant or breastfeeding
- •Patients with history of untreated hepatitis B or who are known carriers of hepatitis B will be excluded from this trial. All subjects will be screened prior to study entry.
- •Concurrent use of other anti-cancer agents or anti-cancer treatments.
研究组 & 干预措施
Phase 1: Pixantrone, 55mg/m^2
Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
干预措施: Bendamustine + Rituximab + Pixantrone (Drug)
Phase 1: Pixantrone, 55mg/m^2
Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 55mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
干预措施: Pegfilgrastim (Drug)
Phase 1: Pixantrone, 85mg/m^2
Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
干预措施: Bendamustine + Rituximab + Pixantrone (Drug)
Phase 1: Pixantrone, 85mg/m^2
Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 85mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
干预措施: Pegfilgrastim (Drug)
Phase 1: Pixantrone, 115mg/m^2
Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
干预措施: Bendamustine + Rituximab + Pixantrone (Drug)
Phase 1: Pixantrone, 115mg/m^2
Bendamustine, 120mg/m2; administered first on Day 1 of each cycle. Rituximab, 375mg/m2; administered second on Day 1 of each cycle. Pixantrone, 115mg/m2; to be administered last, 4-6 hours after bendamustine, on Day 1 of each cycle Pegfilgrastim, 6mg; administered on Day 2 of each cycle
干预措施: Pegfilgrastim (Drug)
结局指标
主要结局
Maximum Tolerated Dose
时间窗: 4 years
Dose-limiting toxicity (DLT) assessments were performed weekly during cycles 1 and 2. A DLT was defined as any grade 3 non-hematologic toxicity that lasted longer than 48 hours, despite proper supportive care, any grade 4 non-hematologic toxicity, or any grade 3 or 4 hematologic toxicity lasting longer than 7 days. Alopecia and febrile neutropenia were not considered DLTs. Any NCI CTC (National Cancer Institute Common Terminology Criteria) v4.03 grade 5 (death) toxicity was considered a DLT. Dose Limiting Toxicities were used as the assessment criteria to determine the Maximum Tolerated Dose (MTD). MTD is presented.
次要结局
- Toxicity(30 days post last dose of study drug)
- Progression Free Survival(From day 1 of treatment to disease progression, death or 5 years, whichever comes first)
- Overall Response(up to 220 days)
- Overall Survival(from day 1 of treatment to death)
研究者
Anne Beaven, MD
Assist Professor of Medicine
Duke University