Enhancing Effect on Tumour Apoptosis With the Combined Use of Pentoxifylline Plus Chemotherapeutical Agents in Pediatrics and AYA Patients With Hodgkin´s Lymphoma
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Peripheral apoptosis (Fortilin)
研究概览
简要总结
Hodgkin's Lymphoma (HL) is a neoplasm that affects the lymph nodes and the lymphatic system. In Mexico, HL is the seventh most incident cancer and the ninth with the highest mortality. It is characterized by the presence of Reed-Sternberg (HRS) cells derived from B cells of the germinal center. They harbor mutations that activate the NF-κB pathway, favoring cell survival and their reprogramming. Currently, the available therapeutic options are chemotherapy and radiotherapy, achieving cure rates of 75% in patients in advanced stages, in which 70% of these are found at the time of diagnosis. The investigators proposed the use of pentoxifylline (PTX) as a therapeutic option to enhance the antitumor effect generated by the treatment since it can increase the efficacy of apoptosis, in vitro and in vivo, induced by doxorubicin, cisplatin, and adriamycin in human leukemic and cervical cancer cells, through inhibition of NF-κB by preventing phosphorylation of serine 32 of the inhibitor κB; it also decreases the expression of Bcl-2 and Bcl-XL, induces the releasement of cytochrome c and caspases 3, 9, and cleavage of caspase 8. The investigators evaluated the effects of PTX during the steroid window phase at induction to remission in pediatric patients with LLA of a recent diagnosis, where it was shown that the combined treatment of prednisone (PRD) with PTX achieves greater percentages of apoptosis compared to individual treatment. In addition, the effect of PTX on the expression of genes associated with apoptosis was evaluated; where it was shown that it activates the intrinsic and extrinsic pathways of apoptosis. Fortilin is a protein whose serum levels increase 2.4 times more after treatment with chemotherapy or radiotherapy in patients with malignancies, so it is considered a specific and sensitive biomarker of early apoptosis in vivo. The present protocol will evaluate the enhancing effect of PTX on tumor apoptosis in combination with chemotherapeutical agents in pediatric and AYA patients with HL. Apoptosis will be measured in vivo by quantifying serum levels of fortilin and cytochrome c in participants before and after treatment by ELISA; as well as an evaluation of the clinical response based on the results of the PET-Scan, overall and event-free survival according to the Kaplan-Meier curves, and the adverse effects associated with the use of PTX according to the common terminology criteria for adverse events and causality algorithms.
详细描述
Hodgkin Lymphoma (HL) is a B-cell-derived neoplasm that involves the lymph nodes and lymphatic system. In Mexico, HL is seventh cancer with the highest incident rates and the ninth with the highest mortality.
The incidence of this pathology has a bimodal distribution, with the first peak of appearance among adolescents and young adults within an age range that goes from 15 to 35 years, followed by a second peak in adults 55 years of age and older.
This neoplasm is characterized by the presence of Reed-Sternberg cells (HRS), which are distinguished by being large with multinucleate or bilobed nuclei and being derived from B lymphocytes of the germinal center. They have a partial loss of the B phenotype and classical lineage markers. They harbor mutations that activate the NF-κB pathway, which regulates antiapoptotic factors, the expression of proinflammatory cytokines, and the reprogramming of B cells.
Patients with HL frequently present asymptomatic, painless, and slowly progressive lymphadenopathy. There may also be systemic symptoms such as B symptoms which are defined by the presence of deep night sweats, unexplained weight loss of >10% of total body weight within the previous 6 months at diagnosis, and persistent or recurrent fever ≥38˚C.
Excisional biopsy of potentially involved lymph nodes is the gold standard for establishing the diagnosis of HL. A histopathological study is performed, in which the presence of diagnostic HRS cells must be found in an adequate microenvironment and the expression of CD30 and CD15.
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
- Triple (Participant, Care Provider, Investigator)
盲法说明
Patients will be stratified at randomization based on their clinical stage at diagnosis, according to the Cotswold classification system, into limited-stage (stage I or II disease without B symptoms and absence of bulky or stage IB disease without bulky disease) and advanced stage (patients with stage II disease with B symptoms or bulky disease, or stage III or IV disease). In addition, a random permutation method with blocks of size 6 will be used, thus creating 5 blocks of size 6 patients each. Each patient will be classified into a specific study group (Group A: conventional treatment plus placebo; group B: conventional treatment plus pentoxifylline).
入排标准
- 年龄范围
- 6 Years 至 35 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Pediatric and AYA (adolescents and young adults) patients (age up to 35 years of either sex) newly diagnosed with Hodgkin lymphoma regardless of clinical stage.
- •Patients with the ability to swallow tablets.
- •Patients who agree to enter the protocol by signing the informed consent personally or by the parent/guardian
排除标准
- •Patients previously treated with chemotherapy, corticoids, and/or radiotherapy
- •History of active acid peptic disease or gastrointestinal bleeding Intolerance to pentoxifylline and in general to xanthines
- •Patients under treatment with anticoagulants, cimetidine, ciprofloxacin or theophylline
- •Patients with severe bleeding, retinal hemorrhage or bleeding diathesis
- •Serious cardiac arrhythmias (E.g. paroxysmal supraventricular tachycardia, congenital AV block, arrhythmias associated with congenital heart disease, digitalis poisoning, postoperative cardiac surgery, hypoxia, hypercapnia, electrolyte disturbances)
- •Patients with hypotension
- •Severe liver failure
- •Moderate to severe renal insufficiency (with a glomerular filtration rate ≤ 30 mL/min)
- •Patients admitted to the Intensive Care Unit at diagnosis
- •Patients with treatment adherence of less than 80%
- •Patients who wish to withdraw from the study or withdraw informed consent
- •Patients who present grade III adverse events related to the drug under study
- •Patients who become pregnant during the study
研究组 & 干预措施
Group A with placebo
Patients with conventional treatment based on the OEPA/COPDAC, ABVD or BEACOPP scheme plus placebo, during the first two cycles of chemotherapy.
干预措施: Placebo (Drug)
Group B with pentoxifylline
Patients with conventional treatment based on the OEPA/COPDAC, ABVD or BEACOPP scheme plus pentoxifylline, during the first two cycles of chemotherapy.
Pentoxifylline dose of 20 mg/kg/day, maximum dose 1200 mg/day
干预措施: Pentoxifylline (Drug)
结局指标
主要结局
Peripheral apoptosis (Fortilin)
时间窗: At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)
3 samples of peripheral venous blood will be obtained from the patients from both study groups before the beginning of treatment (day 0), at the end of the first cycle of chemotherapy (day 30), and the end of the second cycle (day 60). Fortilin plasma levels will be determined using the translationally controlled human tumor protein ELISA kit (TPT1), according to the manufacturer's specifications. The optical density will be determined using a Biotek Synergy™ HT plate reader at a wavelength of 450nm. The results will be presented as the mean ± standard deviation in pg/mL. In the 3 blood samples that will be taken from the participants, the same marker will be evaluated. As it is the same variable, it will be measured with the same unit of measure (pg/mL) for the 3 blood samples. At the end of the study, it will be evaluated if there was any change in the plasma levels of fortilin (in pg/mL), either an increase or a decrease.
Peripheral apoptosis (Cytochrome c)
时间窗: At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)
3 samples of peripheral venous blood will be obtained from the patients from both study groups before the beginning of treatment (day 0), at the end of the first cycle of chemotherapy (day 30), and the end of the second cycle (day 60). Cytochrome c plasma levels will be determined using the human cytochrome c ELISA kit, according to the manufacturer's specifications. The optical density will be determined using a Biotek Synergy™ HT plate reader at a wavelength of 450nm. The results will be presented as the mean ± standard deviation in pg/mL. In the 3 blood samples that will be taken from the participants, the same marker will be evaluated. As it is the same variable, it will be measured with the same unit of measure (pg/mL) for the 3 blood samples. At the end of the study, it will be evaluated if there was any change in the plasma levels of fortilin (in pg/mL), either an increase or a decrease.
次要结局
- Assessment of the clinical response by positron emission tomography (PET)(At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days))
- Assessment of the severity of adverse effects(A 24-month follow-up will be given after finishing the corresponding treatment, at that time, the adverse effects will be studied.)
- Correlation of adverse effects with pentoxifylline(A 24-month follow-up will be given after finishing the corresponding treatment, at that time, the adverse effects will be studied.)
- Assessment of the clinical response by Computerized Axial Tomography(At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days))
- Assessment of the clinical response(At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days))
- Determination of event-free survival(A 24-month follow-up will be given after completion of the corresponding treatment, at the time, survival will be evaluated.)
研究者
Ramón Óscar González-Ramella, Ph.D
Titular Research Professor
University of Guadalajara