Pentoxifylline In Pediatric Acute Lymphoblastic Leukemia During Induction

Acute Lymphoblastic Leukemia Clinical Trial

— PTX-II  

Official title:

SAFETY AND EFFICACY OF PENTOXIFYLLINE VERSUS PLACEBO ADMINISTERED AS APOPTOSIS INDUCTOR DURING REMISSION INDUCTION PHASE OF PEDIATRIC PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02451774
• Other study ID #: IICIA -PTX02
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: January 2015
• Est. completion date: December 2020

Study information

• Verified date: May 2018
• Source: University of Guadalajara
• Contact: Monzerrat Pardo Zepeda, MD
• Phone: +5213311946817
• Email: monzepardo[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Recent advances in acute lymphoblastic leukemia treatment are based on a cytotoxic drug combination. Measurement of minimal residual disease in bone marrow samples at day 14 of treatment is the most powerful early predictive indicator of further relapse, and it can be applied practically to all patients with acute lymphoblastic leukemia. Even more so, it has been observed that patients who present negative minimal residual disease in bone marrow samples at day 7 during induction have a better prognosis than those achieving this at day 14.

Relapse represents the main cause of treatment failure that related in the extreme with resistance to apoptosis, defining the latter as the principal mechanism of programmed cell death; it is also related with the induction of leukemic cells to senescent arrest.

Pentoxifylline is a methyl-xanthine byproduct considered an unspecific inhibitor of phosphodiesterase. It inhibits nuclear factor-kappa-beta activation by different mechanisms and stimulates apoptosis induced by different drugs; thus, it can optimize the antineoplastic effect of actual treatments in order to increase the apoptosis of leukemic cells. This effect might improve the prognosis of these patients.

Evaluate the safety and effect of Pentoxifylline together with antineoplastic drugs in order to study increased apoptosis and decreased senescence during the remission induction phase in pediatric patients with newly diagnosed acute lymphoblastic leukemia. To achieve this propose, we will divide patients in two groups, who will receive pentoxifylline or placebo depending on the group, in addition to conventional treatment according to the protocol standard chemotherapy schema for pediatric patients with acute lymphoblastic leukemia at our institution during the remission induction phase. In addition, we will test whether the study group exerts an impact on reaching remission earlier as compared with the control group.

Description:

This study will be controlled, double-blind clinical trial versus placebo, with random assignment to evaluate the effect of pentoxifylline on apoptosis and senescence of leukemic blasts from remission induction in pediatric patients with newly diagnosed acute lymphoblastic leukemia, as well as to address pentoxifylline efficacy and safety in this group of patients.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 44
• Est. completion date: December 2020
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

Inclusion Criteria:

• Pediatric and teenaged patients of both genders =18 years of age with newly diagnosed acute lymphoblastic leukemia in accordance with French-American-British criteria and under immunophenotypical classification and paired within the risk-classification group.

• Patients with =20 kg of weight at the time of treatment assignment.

• Patients who are able to swallow the medicine

• Patients agreeing to enter the protocol by the signing of informed consent by the parent

• Patients who could give their assent to enter the protocol

• The parent or guardian must be able to read.

Exclusion Criteria:

• Patients with treatment adherence of =80 percent

• Patients or their parents who decide to abandon the study or who withdraw consent for participation

• Patients who present grade III or higher adverse event.

• Patients previously treated with chemotherapy and/or radiotherapy

• History of peptic acid disease or gastrointestinal bleeding

• Known pentoxifylline intolerance and general intolerance to xanthine, caffeine or theophylline

• Patients in treatment with anticoagulants, Cimetidine, Ciprofloxacin, or Theophylline

• Patients with Down syndrome

• Patients with several bleeding or extensive retinal hemorrhage, several cardiac arrhythmias (paroxysmal supraventricular tachycardia, congenital atrioventricular block, arrhythmias associated with congenital heart disease, digital poisoning, and patients after cardiac surgery, hypoxia, hypercapnia, and electrolyte disturbances)

• Patients with hypotension

• Several liver failures

• Bleeding diathesis (for bleeding disorders or anticoagulant medication)

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Pentoxifylline Plus Chemotherapy
Pentoxifylline 10 to 20 milligrams per kilogram, daily, for up to 32 days Chemotherapy: Prednisone 40 milligrams per square meter per day, orally, day 5-32. Vincristine 1.5 milligrams per square meter per week, intravenously, day 5, 12, 19, 26. Daunorubicin 25 milligrams per square meter per week, intravenously, days 5; 12. L-asparaginase 10,000 units for square meter, intramuscular, days 6, 8, 10, 12, 14, 16, 19, 21, 23. Cyclophosphamide 1000 milligrams per square meter per dose intravenously, day 26. Cytarabine 75 milligrams per square meter per dose intravenously, days 27-30, 34-37. 6-Mercaptopurine 60 milligrams per square meter per dose, orally, days 26-39, Mix: Methotrexate 8-12 milligrams, Hydrocortisone 16-24 milligrams and Cytarabine 24-36 milligrams, intrathecal, day 19.
• Placebo Plus Chemotherapy
Placebo daily, for up to 32 days Chemotherapy: Prednisone 40 milligrams per square meter per day, orally, day 5-32. Vincristine 1.5 milligrams per square meter per week, intravenously, day 5, 12, 19, 26. Daunorubicin 25 milligrams per square meter per week, intravenously, days 5; 12. L-asparaginase 10,000 units for square meter, intramuscular, days 6, 8, 10, 12, 14, 16, 19, 21, 23. Cyclophosphamide 1000 milligrams per square meter per dose intravenously, day 26. Cytarabine 75 milligrams per square meter per dose intravenously, days 27-30, 34-37. 6-Mercaptopurine 60 milligrams per square meter per dose, orally, days 26-39, Mix: Methotrexate 8-12 milligrams, Hydrocortisone 16-24 milligrams and Cytarabine 24-36 milligrams, intrathecal, day 19.

Locations

Country	Name	City	State
Mexico	Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"	Guadalajara	Jalisco

Sponsors (4)

Lead Sponsor	Collaborator
Ramón Óscar González-Ramella, Ph.D	Centro de Investigacion Biomedica de Occidente, Hospital Civil Juan I. Menchaca, Instituto de Investigacion en Cancer de la Infancia y la Adolescencia

Country where clinical trial is conducted

Mexico, 

References & Publications (14)

Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol. 2005 Sep 10;23(26):6306-15. Review. — View Citation

Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007 Jan;115(1):138-45. Review. Erratum in: Environ Health Perspect. 2010 Sep;118(9):A380. — View Citation

Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705. doi: 10.1146/annurev-physiol-030212-183653. Epub 2012 Nov 8. Review. — View Citation

Chauhan PS, Bhushan B, Singh LC, Mishra AK, Saluja S, Mittal V, Gupta DK, Kapur S. Expression of genes related to multiple drug resistance and apoptosis in acute leukemia: response to induction chemotherapy. Exp Mol Pathol. 2012 Feb;92(1):44-9. doi: 10.10 — View Citation

Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012 Jan 5;119(1):34-43. doi: 10.1182/blood-2011-04-347872. Epub 2011 Nov 15. — View Citation

Hernandez-Flores G, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy Adel C, de Celis-Carrillo R, del Toro-Arreola S, Castellanos-Esparza YC, Bravo-Cuellar A. Pentoxifylline sensitizes human cervical tumor cells t — View Citation

Herr I, Debatin KM. Cellular stress response and apoptosis in cancer therapy. Blood. 2001 Nov 1;98(9):2603-14. Review. — View Citation

Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, Jerez A, Przychodzen B, Bupathi M, Guinta K, Afable MG, Sekeres MA, Padgett RA, Tiu RV, Maciejewski JP. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis — View Citation

Pérez-Saldivar ML, Fajardo-Gutiérrez A, Bernáldez-Ríos R, Martínez-Avalos A, Medina-Sanson A, Espinosa-Hernández L, Flores-Chapa Jde D, Amador-Sánchez R, Peñaloza-González JG, Alvarez-Rodríguez FJ, Bolea-Murga V, Flores-Lujano J, Rodríguez-Zepeda Mdel C, — View Citation

Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011 Feb 10;29(5):551-65. doi: 10.1200/JCO.2010.30.7405. Epub 2011 Jan 10. Review. Erratum in: J Clin Oncol. 2011 — View Citation

Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008 Mar 22;371(9617):1030-43. doi: 10.1016/S0140-6736(08)60457-2. Review. — View Citation

Reuter S, Gupta SC, Kannappan R, Aggarwal BB. WITHDRAWN: Evidence for the critical roles of NF-?B p65 and specificity proteins in the apoptosis-inducing activity of proteasome inhibitors in leukemia cells. Biochim Biophys Acta. 2012 Jan 10. [Epub ahead of — View Citation

Sankari SL, Masthan KM, Babu NA, Bhattacharjee T, Elumalai M. Apoptosis in cancer--an update. Asian Pac J Cancer Prev. 2012;13(10):4873-8. Review. — View Citation

Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011 Sep 26;30:87. doi: 10.1186/1756-9966-30-87. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Gene expression measure by Microarray and Semi-quantitative Polymerase Chain Reaction.	Fold change by microarray and Semi-quantitative Polymerase Chain Reaction.	Up to 28 days after initiation of chemotherapy for remission induction.
Primary	Apoptosis measure by Flow Cytometry	Percentage of apoptotic cells by Flow Cytometry	Up to 28 days after initiation of chemotherapy for remission induction
Secondary	Senescence measure by Flow Cytometry	Percentage of senescent blasts by Flow Cytometry	Up to 28 days after initiation of chemotherapy for remission induction.
Secondary	Safety measure by Common Terminology Criteria for Adverse Events version 4.0	Percentage of adverse events grading table is a list of common terms and severity (intensity) of parameters used to describe adverse events occurring in Common Terminology Criteria for Adverse Events version 4.0	Evaluate frequency adverse events with pentoxifylline up to 6 weeks