Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia

NCT05326984 | Unknown

• 1 other identifier: DI/21/505/03/10
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Acute lymphoblastic leukemia, is the most frequent cancer in children and adolescents. Some genes have been described to produce drug resistance, as ABCB1 probably by lack of activation of AMPK. Some manuscripts have shown that metformin has antitumoral activity, mainly by activation of AMPK. This is an experimental one center trial, that pretend analyze the effect of metformin at a dose of 1000mgm2 per day, on the expression of the ABCB1 and AMPK genes, when is added to conventional induction remission chemotherapy in newly diagnosed adolescents with acute lymphoblastic leukemia.

Conditions

Acute Lymphoblastic Leukemia

Keywords

adolescents; metformin; ABCB1; AMPK

Outcome Measures

Primary Outcomes (2)

• Decrease of ABCB1 gene expression

  During the trial ABCB1 gene expression is measure by rt-PCR in mononuclear cells in peripheral blood, at at the beginning of treatment and end of the remission induction

  The assessment of ABCB1 gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33

• Increase of AMPK gene expression

  During the trial AMPK gene expression is measure by rt-PCR in mononuclear cells in peripheral blood, at athe beginning and end of the remission induction.

  The assessment of AMPK gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33

Secondary Outcomes (2)

• Overall survival

  From randomization and initiation of the treatment until the date of death from any cause, assessed up to 2 years

• Event free survival

  From randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed upt to 2 years

Study Arms (2)

Control group

NO INTERVENTION

This subjets will receive conventional chemotherapy alone. The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60mgm2SCD. The proper remission induction phase consist in prednisone 60mgm2 daily from day 0 to 28; Vincristine 1.5mgm2 on days 0, 7, 14 and 21; Doxorubicin 25mgm2 on days 0, 7, 21; L-asparaginase 10, 000 Um2 on days 2, 4, 6, 8, 10 and 12. Etoposide 300mgm2 and cytarabine 300mgm2 on days 22, 25 and 29. Intrathecal chemotherapy is administered on days 0, 7, 14 and 21.

Interventional group

EXPERIMENTAL

This group will receive conventional chemotherapy plus metformin 1000mgm2 per day, with maximum dose of 850mg three times a day, from day -7 to the end of the remission induction period. The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60mgm2SCD. The proper remission induction phase consist in prednisone 60mgm2 daily from day 0 to 28; Vincristine 1.5mgm2 on days 0, 7, 14 and 21; Doxorubicin 25mgm2 on days 0, 7, 21; L-asparaginase 10, 000 Um2 on days 2, 4, 6, 8, 10 and 12. Etoposide 300mgm2 and cytarabine 300mgm2 on days 22, 25 and 29. Intrathecal chemotherapy is administered on days 0, 7, 14 and 21.

Drug: Metformin

Interventions

Metformin DRUG

Metformin will be administered orally to the experimental group by randomization at a dose of 1000mgm2 per day, with maximum dose of 850mg three times a day, from day -7 to the end of the remission induction period.

Interventional group

Eligibility Criteria

• Age: 10 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Newly diagnosed adolescents with acute lymphoblastic leukemia by morphology analysis in bine marrow
• Adolescents between 10 and 21 years old
• Participants with the informed consent signed by themselves and the parents or legally authorized representative.

You may not qualify if:

• Participants with previous use of any antineoplastic drug
• Down syndrome patients

Sponsors & Collaborators

• Hospital General de Mexico: lead

Study Sites (1)

Hospital General de México

Mexico City, 06720, Mexico

RECRUITING

Related Publications (12)

• Smith MA, Seibel NL, Altekruse SF, Ries LA, Melbert DL, O'Leary M, Smith FO, Reaman GH. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol. 2010 May 20;28(15):2625-34. doi: 10.1200/JCO.2009.27.0421. Epub 2010 Apr 19.

  PMID: 20404250 BACKGROUND

• Rivera-Luna R, Shalkow-Klincovstein J, Velasco-Hidalgo L, Cardenas-Cardos R, Zapata-Tarres M, Olaya-Vargas A, Aguilar-Ortiz MR, Altamirano-Alvarez E, Correa-Gonzalez C, Sanchez-Zubieta F, Pantoja-Guillen F. Descriptive Epidemiology in Mexican children with cancer under an open national public health insurance program. BMC Cancer. 2014 Oct 29;14:790. doi: 10.1186/1471-2407-14-790.

  PMID: 25355045 BACKGROUND

• Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, Reaman GH, Carroll WL. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012 May 10;30(14):1663-9. doi: 10.1200/JCO.2011.37.8018. Epub 2012 Mar 12.

  PMID: 22412151 BACKGROUND

• Wolfson JA, Richman JS, Sun CL, Landier W, Leung K, Smith EP, O'Donnell M, Bhatia S. Causes of Inferior Outcome in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: Across Oncology Services and Regardless of Clinical Trial Enrollment. Cancer Epidemiol Biomarkers Prev. 2018 Oct;27(10):1133-1141. doi: 10.1158/1055-9965.EPI-18-0430. Epub 2018 Sep 27.

  PMID: 30262597 BACKGROUND

• Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001 Jul;11(7):1156-66. doi: 10.1101/gr.184901.

  PMID: 11435397 BACKGROUND

• Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006 Mar;5(3):219-34. doi: 10.1038/nrd1984.

  PMID: 16518375 BACKGROUND

• Rahgozar S, Moafi A, Abedi M, Entezar-E-Ghaem M, Moshtaghian J, Ghaedi K, Esmaeili A, Montazeri F. mRNA expression profile of multidrug-resistant genes in acute lymphoblastic leukemia of children, a prognostic value for ABCA3 and ABCA2. Cancer Biol Ther. 2014 Jan;15(1):35-41. doi: 10.4161/cbt.26603. Epub 2013 Oct 21.

  PMID: 24145140 BACKGROUND

• Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010 Jul;33(7):1674-85. doi: 10.2337/dc10-0666.

  PMID: 20587728 BACKGROUND

• Trucco M, Barredo JC, Goldberg J, Leclerc GM, Hale GA, Gill J, Setty B, Smith T, Lush R, Lee JK, Reed DR. A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin. Pediatr Blood Cancer. 2018 Sep;65(9):e27224. doi: 10.1002/pbc.27224. Epub 2018 Jun 1.

  PMID: 29856514 BACKGROUND

• Leclerc GM, Leclerc GJ, Kuznetsov JN, DeSalvo J, Barredo JC. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS One. 2013 Aug 23;8(8):e74420. doi: 10.1371/journal.pone.0074420. eCollection 2013.

  PMID: 24009772 BACKGROUND

• Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012 Mar 29;48(3):R31-43. doi: 10.1530/JME-12-0007. Print 2012 Jun.

  PMID: 22355097 BACKGROUND

• Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, Kwon KI, Kim BH, Kim SK, Song GY, Jeong TC, Jeong HG. Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol. 2011 Mar;162(5):1096-108. doi: 10.1111/j.1476-5381.2010.01101.x.

  PMID: 21054339 BACKGROUND

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Metformin

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Adolfo Martinez Tovar, PhD

  Hospital General de méxico

  STUDY CHAIR

Central Study Contacts

Daniel Ortiz Morales, MSc

CONTACT

+52 552789200; dr.ortiz_morales@outlook.com

Adolfo Martinez Tovar, PhD

CONTACT

+52 552789200; mtadolfo73@hotmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of pediatric hematology & oncology

Model Details: The patients are randomized assigned to one of two groups. One group (control group) will receive conventional chemotherapy during remission induction, the other group will receive conventional chemotherapy plus metformin 1000mgm2 per day during the remission induction.

Study Record Dates

• First Submitted: February 15, 2022
• First Posted: April 14, 2022
• Study Start: February 9, 2021
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: April 14, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)