NCT02451774

Brief 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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
44

participants targeted

Target at P25-P50 for phase_2

Timeline
Completed

Started Jan 2015

Longer than P75 for phase_2

Geographic Reach
1 country

1 active site

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

January 1, 2015

Completed
1 month until next milestone

First Submitted

Initial submission to the registry

February 9, 2015

Completed
3 months until next milestone

First Posted

Study publicly available on registry

May 22, 2015

Completed
4.5 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2019

Completed
1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2020

Completed
Last Updated

May 9, 2018

Status Verified

May 1, 2018

Enrollment Period

4.9 years

First QC Date

February 9, 2015

Last Update Submit

May 7, 2018

Conditions

Acute Lymphoblastic Leukemia

Keywords

pediatricapoptosis

Outcome Measures

Primary Outcomes (1)

  • Apoptosis measure by Flow Cytometry

    Percentage of apoptotic cells by Flow Cytometry

    Up to 28 days after initiation of chemotherapy for remission induction

Secondary Outcomes (2)

  • Senescence measure by Flow Cytometry

    Up to 28 days after initiation of chemotherapy for remission induction.

  • Safety measure by Common Terminology Criteria for Adverse Events version 4.0

    Evaluate frequency adverse events with pentoxifylline up to 6 weeks

Other Outcomes (1)

  • Gene expression measure by Microarray and Semi-quantitative Polymerase Chain Reaction.

    Up to 28 days after initiation of chemotherapy for remission induction.

Study Arms (2)

Pentoxifylline Plus Chemotherapy

EXPERIMENTAL

Pentoxifylline: 10-20 milligrams per kilogram, doses daily by oral, for 30 days. Chemotherapy: Prednisone, Vincristine, Daunorubicin, L-asparaginase, Cyclophosphamide, Cytarabine, 6-Mercaptopurine, Methotrexate, Hydrocortisone and Cytarabine

Drug: Pentoxifylline Plus Chemotherapy

Placebo Plus Chemotherapy

PLACEBO COMPARATOR

Placebo: double blind period, one doses daily for 30 days. Chemotherapy: Prednisone, Vincristine, Daunorubicin, L-asparaginase, Cyclophosphamide, Cytarabine, 6-Mercaptopurine, Methotrexate, Hydrocortisone and Cytarabine

Drug: Placebo Plus Chemotherapy

Interventions

Pentoxifylline Plus ChemotherapyDRUG

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.

Also known as: Oxpentifylline
Pentoxifylline Plus Chemotherapy
Placebo Plus ChemotherapyDRUG

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.

Also known as: Placebo
Placebo Plus Chemotherapy

Eligibility Criteria

Age1 Year - 18 Years
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64)

You may qualify if:

  • 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.

You may not qualify if:

  • 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)

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"

Guadalajara, Jalisco, 44340, Mexico

RECRUITING

Related Publications (15)

  • 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. Blood. 2012 Apr 5;119(14):3203-10. doi: 10.1182/blood-2011-12-399774. Epub 2012 Feb 9.

    PMID: 22323480RESULT

  • 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.

    PMID: 22086414RESULT

  • Perez-Saldivar ML, Fajardo-Gutierrez A, Bernaldez-Rios R, Martinez-Avalos A, Medina-Sanson A, Espinosa-Hernandez L, Flores-Chapa Jde D, Amador-Sanchez R, Penaloza-Gonzalez JG, Alvarez-Rodriguez FJ, Bolea-Murga V, Flores-Lujano J, Rodriguez-Zepeda Mdel C, Rivera-Luna R, Dorantes-Acosta EM, Jimenez-Hernandez E, Alvarado-Ibarra M, Velazquez-Avina MM, Torres-Nava JR, Duarte-Rodriguez DA, Paredes-Aguilera R, Del Campo-Martinez Mde L, Cardenas-Cardos R, Alamilla-Galicia PH, Bekker-Mendez VC, Ortega-Alvarez MC, Mejia-Arangure JM. Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology. BMC Cancer. 2011 Aug 17;11:355. doi: 10.1186/1471-2407-11-355.

    PMID: 21846410RESULT

  • Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007 Jan;115(1):138-45. doi: 10.1289/ehp.9023.

    PMID: 17366834RESULT

  • 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.

    PMID: 18358930RESULT

  • 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.

    PMID: 21220611RESULT

  • Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011 Sep 26;30(1):87. doi: 10.1186/1756-9966-30-87.

    PMID: 21943236RESULT

  • Herr I, Debatin KM. Cellular stress response and apoptosis in cancer therapy. Blood. 2001 Nov 1;98(9):2603-14. doi: 10.1182/blood.v98.9.2603.

    PMID: 11675328RESULT

  • 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.

    PMID: 23140366RESULT

  • 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. doi: 10.7314/apjcp.2012.13.10.4873.

    PMID: 23244073RESULT

  • 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: 10.1016/j.yexmp.2011.09.004. Epub 2011 Oct 19.

    PMID: 22037714RESULT

  • Reuter S, Gupta SC, Kannappan R, Aggarwal BB. WITHDRAWN: Evidence for the critical roles of NF-kappaB p65 and specificity proteins in the apoptosis-inducing activity of proteasome inhibitors in leukemia cells. Biochim Biophys Acta. 2012 Jan 10:10.1016/j.bbadis.2012.01.002. doi: 10.1016/j.bbadis.2012.01.002. Online ahead of print.

    PMID: 22265847RESULT

  • 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 to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence. BMC Cancer. 2011 Nov 10;11:483. doi: 10.1186/1471-2407-11-483.

    PMID: 22074157RESULT

  • Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol. 2005 Sep 10;23(26):6306-15. doi: 10.1200/JCO.2005.05.047.

    PMID: 16155013RESULT

  • Salceda-Rivera V, Ortiz-Lazareno PC, Hernandez-Flores G, Vazquez-Urrutia JR, Meza-Arroyo J, Pardo-Zepeda M, Romo-Rubio H, Barba-Barba C, Sanchez-Zubieta F, Barron-Gallardo CA, Gonzalez-Ramella O, Bravo-Cuellar A. Very early remission and increased apoptosis with the use of Pentoxifylline in children with acute lymphoblastic leukemia. Front Oncol. 2024 Oct 3;14:1401262. doi: 10.3389/fonc.2024.1401262. eCollection 2024.

    PMID: 39421449DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

PentoxifyllineDrug Therapy

Condition Hierarchy (Ancestors)

Leukemia, LymphoidLeukemiaNeoplasms by Histologic TypeNeoplasmsHematologic DiseasesHemic and Lymphatic DiseasesLymphoproliferative DisordersLymphatic DiseasesImmunoproliferative DisordersImmune System Diseases

Intervention Hierarchy (Ancestors)

TheobromineXanthinesPurinonesPurinesHeterocyclic Compounds, 2-RingHeterocyclic Compounds, Fused-RingHeterocyclic CompoundsTherapeutics

Study Officials

  • Ramón O. Gonzalez Ramella, PhD

    Instituto de Investigacion de Cancer de la Infancia y la Adolescencia

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Monzerrat Pardo Zepeda, MD

CONTACT

+5213311946817monzepardo@hotmail.com

Fernando A. Sanchez Zubieta, MD

CONTACT

+5213314663092fernandos59@hotmail.com

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
PhD in immunology

Study Record Dates

First Submitted

February 9, 2015

First Posted

May 22, 2015

Study Start

January 1, 2015

Primary Completion

December 1, 2019

Study Completion

December 1, 2020

Last Updated

May 9, 2018

Record last verified: 2018-05

Locations

ME(1)