A Rand. Trial Comp Higher Doses of Rituximab (Rituxan) With Standard Doses of Rituxan in Combination With CVP (Cyclophosphamide, Vincristine, and Prednisone) in Patients With Chronic ITP Who Have Failed/Relapsed After Rituxan Treatment
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Efficacy of Higher Double Doses of Rituxan and of Standard Dose of Rituxan + Cyclophosphamide, Vincristine, Prednisone
研究概览
简要总结
This study is designed to compare the efficacy and safety of higher doses of Rituxan with a regimen combining standard doses of Rituxan + CVP in patients with chronic ITP who did not respond to or relapsed after standard doses of Rituxan. Patients eligible for this protocol will be stratified into two subgroups according to their initial response to Rituxan.
详细描述
The rationale for using chemotherapy in combination with Rituximab:
Since Rituximab is an anti-B cell therapy, in order to improve the rate of durable responses beyond the 32% (18 of 57) seen with Rituximab alone, it seems appropriate to combine it with a therapy that would also target T cells and/or macrophages. Our plan is therefore to combine Rituximab with a standard chemotherapy (CHOP)-like regimen as previously successfully tested in patients with follicular or diffuse large-B-cell lymphomas 13-15. The "CHOP" chemotherapy regimen is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (or prednisolone) that has been considered the "gold standard" for treating lymphomas for more than 20 years.
This combination of medications was used in a Hodgkin's patient with refractory ITP and became the template for developing the use of cyclophosphamide, vincristine, and prednisone for ITP as initially reported in 1993. Since reports on doxorubicin efficacy by itself in ITP are only anecdotal 16 and this drug has a potential cardiac toxicity, a CVP regimen (namely a combination of cyclophosphamide + vincristine and prednisone) should be similar in efficacy to CHOP in patients with ITP and have less toxicity. Indeed, the efficacy of such a chemotherapy12 as well as pulses cyclophosphamide therapy alone11 have already been reported in patients with refractory ITP.
Since attempts to increase the efficacy of CHOP by increasing the doses or adding other cytotoxic drugs have failed, a new therapeutic strategy combining CHOP with Rituxan has been successfully developed in the last few years in various types of B-cell lymphomas 13-15. In elderly patients with diffuse large-B-cell lymphoma, the addition of Rituxan to standard CHOP chemotherapy significantly reduced the risk of treatment failure and deaths without increasing toxicity 13. Moreover, in autoimmune disorders, there are few preliminary data suggesting that Rituxan and cyclophopshamide given in combination could be effective and relatively safe in patients with active rheumatoid arthritis 17.
Therefore, the rationale for combining Rituxan with a CHOP-like regimen in ITP is threefold:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 12 Years 至 100 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients will be eligible to participate in the study if they:
- •Have chronic ITP19 (> 6 months duration)
- •Have received Rituximab a minimum of 3 months prior to entry
- •Have received no more than 2 courses of Rituximab at standard dose separated by a minimum of 12 weeks
- •Have not achieved a durable response to Rituximab, with platelet counts < 30,000/ml when not supported by other treatment
- •Have a platelet count of < 30,000/ul on two separate occasions 1-2 weeks apart within the past month prior to the inclusion
- •We will allow patients who do not have 2 platelet counts < 30,000 on two separate occasions 1-2 weeks apart in the past month, as long as they have either Evan's Syndrome or autoimmune neutropenia (have hemoglobin < 10 g/dL and reticulocytes > 4%, or an absolute neutrophil count < 1.0 K/uL twice within 1 month)
- •Are age ≥ 10 years old
- •Male and Female
- •Had a splenectomy at least 60 days prior to study entry, or a contraindication to splenectomy
- •Give written informed consent
- •Use an effective means of contraception during treatment and for six months after completion of treatment
- •Have negative serum pregnancy test, for all women who are able to have children, within 14 days prior to study entry
排除标准
- •Male and female subjects will be ineligible to participate if they:
- •Received prior treatment with cyclophosphamide within the last 3 months
- •Received prior treatment with > 4 infusions of vinca alkaloids within the 6 months
- •Had previous or concomitant malignancy other than basal cell or squamous cell carcinoma of the skin, carcinoma-in-situ of the cervix, or other malignancy for which the patient had not been disease-free for at least 5 years
- •Have a HIV infection
- •Have hepatitis Bs antigen positivity or active hepatitis C infection
- •Have an absolute neutrophil count < 1.000/mm3 at study entry (unless related to autoimmune neutropenia)
- •Have a Hemoglobin level < 10 g/dl other than caused by thalassemia trait, iron deficiency or autoimmune hemolytic anemia (patients with Evan's syndrome will not be excluded)
- •Have an impaired renal function as indicated by a serum creatinine level > 2.0 mg/dL
- •Have an inadequate liver function as indicated by a total bilirubin level > 2.0 mg/dL and/or an AST or ALT level > 3x upper limit of normal
- •Have active infection requiring antibiotic therapy within 7 days prior to study entry
- •Are pregnant or lactating women, or plan to become pregnant or impregnated within 12 months of receiving study drug
- •Have had a prior severe reaction to Rituximab, leading to discontinuation of treatment
- •Have a New York Heart Classification III or IV heart disease
- •Have a history of severe psychiatric disorder or are unable to comply with study and follow-up procedures
研究组 & 干预措施
Rituximab, Cyclophosphamide, Vincristine, Prednisone
'Standard Dose of Rituximab administered with C, V, P (CVP)'
Interventions: Rituximab will be administered as an IV infusion at the standard dose of 375 mg/m2 for 4 doses at standard rates and use of premedication. The schedule will be to give the first rituximab infusion 5 days (± 3 days) prior to first administration of CVP, and the following 3 infusions will be given on the same day as the 3 cycles of C, V, P. On those days, the IV Cyclophosphamide and Vincristine will be given first so that the administration of fluids with the rituximab can be used as post-cyclophosphamide hydration, Cyclophosphamide dosing will be 750mg/m2 (maximum 2000mg), vincristine 1.4 mg/m2 (up to 1.6 mg), prednisone 100mg po daily for 5 days.
干预措施: Rituxan, Cyclophosphamide, Vincristine, Prednisone (Drug)
Higher Dose of Rituximab
In this arm, Rituximab will be administered at a dose of 750 mg/m2 once a week x 4 consecutive weeks (4 infusions in total). We will perform EKG monitor tracings before, during and after Rituxan infusions. This will be a single-lead tracing that will allow us to look at the Q-T interval.
干预措施: Higher Dose of Rituximab (Drug)
结局指标
主要结局
Efficacy of Higher Double Doses of Rituxan and of Standard Dose of Rituxan + Cyclophosphamide, Vincristine, Prednisone
时间窗: 2 years
Outcome measure was determined by comparing the study participants' historical responses to their initial treatment of rituximab at standard dose/regimen without "enhancement" (based on duration of response and type of response) to the participants response to their study treatment responses. Thus each patient was his or her own control although all study treatments included standard dose rituximab treatments (one at double the dose and one with additional treatments).
次要结局
- Number of Participants With SAEs(2 years)
- Relative Efficacy of the 2 Groups(2 years)