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Pentoxifylline In Pediatric Acute Lymphoblastic Leukemia During Induction (PTX-II)

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ClinicalTrials.gov Identifier: NCT02451774
Recruitment Status : Recruiting
First Posted : May 22, 2015
Last Update Posted : May 9, 2018
Sponsor:
Collaborators:
Instituto de Investigacion en Cancer de la Infancia y la Adolescencia
Hospital Civil Juan I. Menchaca
Centro de Investigacion Biomedica de Occidente
Information provided by (Responsible Party):
Ramón Óscar González-Ramella, Ph.D, University of Guadalajara

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.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Drug: Pentoxifylline Plus Chemotherapy Drug: Placebo Plus Chemotherapy Phase 2 Phase 3

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: SAFETY AND EFFICACY OF PENTOXIFYLLINE VERSUS PLACEBO ADMINISTERED AS APOPTOSIS INDUCTOR DURING REMISSION INDUCTION PHASE OF PEDIATRIC PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA
Study Start Date : January 2015
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Pentoxifylline Plus Chemotherapy

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
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.
Other Name: Oxpentifylline

Placebo Comparator: Placebo Plus Chemotherapy
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
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.
Other Name: Placebo




Primary Outcome Measures :
  1. Apoptosis measure by Flow Cytometry [ Time Frame: Up to 28 days after initiation of chemotherapy for remission induction ]
    Percentage of apoptotic cells by Flow Cytometry


Secondary Outcome Measures :
  1. Senescence measure by Flow Cytometry [ Time Frame: Up to 28 days after initiation of chemotherapy for remission induction. ]
    Percentage of senescent blasts by Flow Cytometry

  2. Safety measure by Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Evaluate frequency adverse events with pentoxifylline up to 6 weeks ]
    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


Other Outcome Measures:
  1. Gene expression measure by Microarray and Semi-quantitative Polymerase Chain Reaction. [ Time Frame: Up to 28 days after initiation of chemotherapy for remission induction. ]
    Fold change by microarray and Semi-quantitative Polymerase Chain Reaction.



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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02451774


Contacts
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Contact: Monzerrat Pardo Zepeda, MD +5213311946817 monzepardo@hotmail.com
Contact: Fernando A. Sanchez Zubieta, MD +5213314663092 fernandos59@hotmail.com

Locations
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Mexico
Hospital Civil de Guadalajara "Dr. Juan I. Menchaca" Recruiting
Guadalajara, Jalisco, Mexico, 44340
Contact: Ramon O Gonzalez Ramella, PhD    5213331719826    glezramella@hotmail.com   
Contact: Fabiola P Medina Barajas, PhD    5213313461917    favyri@hotmail.com   
Sponsors and Collaborators
Ramón Óscar González-Ramella, Ph.D
Instituto de Investigacion en Cancer de la Infancia y la Adolescencia
Hospital Civil Juan I. Menchaca
Centro de Investigacion Biomedica de Occidente
Investigators
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Principal Investigator: Ramón O. Gonzalez Ramella, PhD Instituto de Investigacion de Cancer de la Infancia y la Adolescencia

Publications of Results:

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Responsible Party: Ramón Óscar González-Ramella, Ph.D, PhD in immunology, University of Guadalajara
ClinicalTrials.gov Identifier: NCT02451774     History of Changes
Other Study ID Numbers: IICIA -PTX02
First Posted: May 22, 2015    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2018

Keywords provided by Ramón Óscar González-Ramella, Ph.D, University of Guadalajara:
pediatric
apoptosis

Additional relevant MeSH terms:
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Neoplasms by Histologic Type
Neoplasms
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Methotrexate
Cytarabine
Mercaptopurine
Prednisone
Vincristine
Daunorubicin
Asparaginase
Pentoxifylline
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents