Acute Lymphoblastic LeukemiaNCT05326984
Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia
A study testing Metformin in people with Acute Lymphoblastic Leukemia, run by Hospital General de Mexico at 1 site in Mexico.
Trial 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. Read more about this study
- Who is it for?
- Ages 10 to 21 years
- Conditions the study is for
- Acute Lymphoblastic Leukemia
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteMexico
- Study dates
- 9 Feb 2021to Dec 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 10 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- Participants with previous use of any antineoplastic drug
- Down syndrome patients
Trial locations and contacts
1 site in 1 country.
Mexico1 site, 1 recruiting
- Recruiting
Hospital General de México
Mexico City, 06720
Daniel Ortiz Morales, MSc, +525527892000 ext. 2037, dr.ortiz_morales@outlook.com
Adolfo Martinez Tovar, PhD, +525527892000 ext. 1162, mtadolfo73@hotmail.com
About this study
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.
Read the detailed description
Acute lymphoblastic leukemia, is the most frequent cancer in children and adolescents. By now, chemotherapy agent combination achieves remission in more than 90% of patients. But, adolescents have an adverse prognosis compared with children.
The multiple drug resistant genes are well known the cause resistance in different cancers, most important of these genes are the ABCB gene family, specially ABCB1. This resistance is also reported in acute lymphoblastic leukemia. Also changes in AMPK (adenosine triphosphate) gene expression is related to antitumor effects within the cell.
Metformin, a biguanide, has demonstrated that decrease the intracellular ATP levels by AMPK activation, and the blockade of the glycoprotein P, product of the ABCB1 gene. Many reports had described the effect of metformin on different cancer types. In adults, the use of metformin has demonstrated to be useful improving the overall and event free survival, related to low ABCB1/MDR1 (multidrug resistance 1) expression and high AMPK expression.
The investigators propose if the metformin has any effect on ABCB1/MDR1 and AMPK during remission induction phase in adolescents with newly diagnosed Acute Lymphoblastic Leukemia.
Hypothesis: If metformin is added to standard chemotherapy during the remission induction in Mexican adolescents with newly diagnosed acute lymphoblastic leukemia, so the mRNA (messenger ribonucleid acid) expression levels of the ABCB1 gene will decrease and the AMPK gene expression will increase at the end of remission induction.
This study pretends to evaluate the effect of the addition of metformin to a standard chemotherapy regimen in the modification of the expression of the ABCB1 and AMPK genes during the remission induction of newly diagnosed adolescents with acute lymphoblastic leukemia.
Also to describe the expression levels of ABCB1 and AMPK of healthy adolescents and those diagnosed with acute lymphoblastic leukemia. Compare the expression level of those genes at diagnosis and at the end of remission induction; and to compare the global and event free survival based on the initial expression of those genes, and the use of metformin.
The investigators proposed an randomized open clinical trial to compare the modification of the expression of the ABCB1 and AMPK genes in adolescents with newly diagnosed acute lymphoblastic leukemia in patients receiving conventional chemotherapy versus conventional chemotherapy plus metformin 1000 mgm2SC per day during the remission induction phase of the treatment.
All patients with new acute lymphoblastic leukemia between 10 and 21 years old are invited to participate, with informed consent authorized. The exclusion criteria includes patients with previous use of steroids or other chemotherapy, and patients with Down syndrome.
The investigators pretend to enroll 10 patients for each group. After the morphological and cytometry diagnosis confirmation of acute lymphoblastic leukemia, the adolescents are invited to participate with informed consent signed by the patients and legally authorized representative.
The samples are obtain from mononuclear cells from peripheral blood, the total RNA (Ribonuceid acid) are obtain by TRIzol ® (Invitrogen(R) Life Technologies). The integrity and purity of the nucleic acid are determined by spectrophotometry. The RNA is frozen at -80ºC until needed. The DNAc (complementary desoxyribonucelic acid) synthesis is made from 2micrograms of RNA, oligonucleotides, dNTPs, buffer, MgCl2, KCl (potassium chloride), and DTT (dithiothreitol) are added to obtain a final volume of 20micrograms. The mix is incubated at 37ºC for 2 minutes and 1microliter of inverse transcriptase, and incubated for 50 minutes at 37ºC. The qRT-PCR (quantitative Real time-plymerase chain reaction) of the genes is made using the genic expression assay TaqMan®. The expression levels are calculated using the 2-delta-delta-Ct method.
The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60 mgm2SCD. The proper remission induction phase consist in prednisone 60 mgm2 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. After the remission induction scheme, bone marrow aspiration is performed to evaluate morphology, if less of 5% of lymphoid blast are reported, the patients continue with consolidation phase with high dose methotrexate and 6 mercaptopurine, and after that the maintenance phase until the end of the protocol.
The intermediate variables are the peripheral blast count on day 0, morphology examination of bone marrow on days 14 and at the end of induction and end of induction MRD (minimal residual disease).
Metformin will be administered 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. The procurement of the peripheral blood samples for determination of the expression od the genes ABCB1 and AMPK will be made on day -7 and at the end of the remission induction. Follow up of the patient will be done to calculate the global and event free survival.
- Conditions
- Acute Lymphoblastic Leukemia
- Being tested
- Metformin
- Keywords
- adolescents, metformin, ABCB1, AMPK
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Metformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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.
Measured: 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
The probability of being alive after the randomization of the subjects. Is going to be measure by Kaplan Meir method, and compare between the expression of ABCB1 and AMPK genes, and the use of metformin with the log rank statistics.
Measured: From randomization and initiation of the treatment until the date of death from any cause, assessed up to 2 years
Event free survival
The probability of being alive without relapse after randomization of the participants. Will be assess by Kaplan Meir statistics, and compare with log rank.
Measured: From randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed upt to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2022
- Study start9 Feb 2021
- Primary completionDec 2023 (estimated)
- Study completionDec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital General de Mexico
- Sponsor type
- Other government
- Responsible party
- Principal investigator, Daniel Ortiz Morales, Hospital General de Mexico
- Investigators
- Adolfo Martinez Tovar, PhD, Study chair, Hospital General de méxico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05326984
- Sponsor's protocol ID
- DI/21/505/03/10
- Status last verified
- Apr 2022
- First submitted
- 15 Feb 2022
- Last updated
- 14 Apr 2022
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: The data is going to be coded, and the relation between data and code are only known by the researches and the IRB (institutional review board).
Publications
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.
PubMed 20404250Rivera-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.
PubMed 25355045Hunger 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.
PubMed 22412151Wolfson 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.
PubMed 30262597Dean 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.
PubMed 11435397Szakacs 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.
PubMed 16518375Rahgozar 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.
PubMed 24145140Giovannucci 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.
PubMed 20587728Trucco 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.
PubMed 29856514Leclerc 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.
PubMed 24009772Dowling 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.
PubMed 22355097Kim 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.
PubMed 21054339
Study at a glance
From the registry record, last updated by the sponsor on 14 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT05326984
- Acronym / sponsor ID
- DI/21/505/03/10
- Conditions
- Acute Lymphoblastic Leukemia
- Keywords
- adolescents, metformin, ABCB1, AMPK
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- Hospital General de MexicoOther government
- Study start
- 9 Feb 2021 (actual)
- Primary completion
- Dec 2023 (estimated)
- Study completion
- Dec 2023 (estimated)
- First posted
- 14 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Acute lymphoblastic leukemia, is the most frequent cancer in children and adolescents. By now, chemotherapy agent combination achieves remission in more than 90% of patients. But, adolescents have an adverse prognosis compared with children.
The multiple drug resistant genes are well known the cause resistance in different cancers, most important of these genes are the ABCB gene family, specially ABCB1. This resistance is also reported in acute lymphoblastic leukemia. Also changes in AMPK (adenosine triphosphate) gene expression is related to antitumor effects within the cell.
Metformin, a biguanide, has demonstrated that decrease the intracellular ATP levels by AMPK activation, and the blockade of the glycoprotein P, product of the ABCB1 gene. Many reports had described the effect of metformin on different cancer types. In adults, the use of metformin has demonstrated to be useful improving the overall and event free survival, related to low ABCB1/MDR1 (multidrug resistance 1) expression and high AMPK expression.
The investigators propose if the metformin has any effect on ABCB1/MDR1 and AMPK during remission induction phase in adolescents with newly diagnosed Acute Lymphoblastic Leukemia.
Hypothesis: If metformin is added to standard chemotherapy during the remission induction in Mexican adolescents with newly diagnosed acute lymphoblastic leukemia, so the mRNA (messenger ribonucleid acid) expression levels of the ABCB1 gene will decrease and the AMPK gene expression will increase at the end of remission induction.
This study pretends to evaluate the effect of the addition of metformin to a standard chemotherapy regimen in the modification of the expression of the ABCB1 and AMPK genes during the remission induction of newly diagnosed adolescents with acute lymphoblastic leukemia.
Also to describe the expression levels of ABCB1 and AMPK of healthy adolescents and those diagnosed with acute lymphoblastic leukemia. Compare the expression level of those genes at diagnosis and at the end of remission induction; and to compare the global and event free survival based on the initial expression of those genes, and the use of metformin.
The investigators proposed an randomized open clinical trial to compare the modification of the expression of the ABCB1 and AMPK genes in adolescents with newly diagnosed acute lymphoblastic leukemia in patients receiving conventional chemotherapy versus conventional chemotherapy plus metformin 1000 mgm2SC per day during the remission induction phase of the treatment.
All patients with new acute lymphoblastic leukemia between 10 and 21 years old are invited to participate, with informed consent authorized. The exclusion criteria includes patients with previous use of steroids or other chemotherapy, and patients with Down syndrome.
The investigators pretend to enroll 10 patients for each group. After the morphological and cytometry diagnosis confirmation of acute lymphoblastic leukemia, the adolescents are invited to participate with informed consent signed by the patients and legally authorized representative.
The samples are obtain from mononuclear cells from peripheral blood, the total RNA (Ribonuceid acid) are obtain by TRIzol ® (Invitrogen(R) Life Technologies). The integrity and purity of the nucleic acid are determined by spectrophotometry. The RNA is frozen at -80ºC until needed. The DNAc (complementary desoxyribonucelic acid) synthesis is made from 2micrograms of RNA, oligonucleotides, dNTPs, buffer, MgCl2, KCl (potassium chloride), and DTT (dithiothreitol) are added to obtain a final volume of 20micrograms. The mix is incubated at 37ºC for 2 minutes and 1microliter of inverse transcriptase, and incubated for 50 minutes at 37ºC. The qRT-PCR (quantitative Real time-plymerase chain reaction) of the genes is made using the genic expression assay TaqMan®. The expression levels are calculated using the 2-delta-delta-Ct method.
The Remission induction chemotherapy includes a steroid pre-phase of 7 days of prednisone 60 mgm2SCD. The proper remission induction phase consist in prednisone 60 mgm2 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. After the remission induction scheme, bone marrow aspiration is performed to evaluate morphology, if less of 5% of lymphoid blast are reported, the patients continue with consolidation phase with high dose methotrexate and 6 mercaptopurine, and after that the maintenance phase until the end of the protocol.
The intermediate variables are the peripheral blast count on day 0, morphology examination of bone marrow on days 14 and at the end of induction and end of induction MRD (minimal residual disease).
Metformin will be administered 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. The procurement of the peripheral blood samples for determination of the expression od the genes ABCB1 and AMPK will be made on day -7 and at the end of the remission induction. Follow up of the patient will be done to calculate the global and event free survival.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| 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 | Drug: MetforminThis 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. |
Who may qualify
- Ages
- 10 to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (2 listed)
- Participants with previous use of any antineoplastic drug
- Down syndrome patients
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminMetformin 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. | Drug | Interventional group |
Primary outcome
Decrease of ABCB1 gene expression
Time frame: The assessment of ABCB1 gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33
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
Increase of AMPK gene expression
Time frame: The assessment of AMPK gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33
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.
2 secondary outcomes
Overall survival
Time frame: From randomization and initiation of the treatment until the date of death from any cause, assessed up to 2 years
Event free survival
Time frame: From randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed upt to 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Apr 2022.
- Background: PubMed 20404250Smith 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.
- Background: PubMed 25355045Rivera-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.
- Background: PubMed 22412151Hunger 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.
- Background: PubMed 30262597Wolfson 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.
- Background: PubMed 11435397Dean 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.
- Background: PubMed 16518375Szakacs 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.
- Background: PubMed 24145140Rahgozar 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.
- Background: PubMed 20587728Giovannucci 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.
- Background: PubMed 29856514Trucco 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.
- Background: PubMed 24009772Leclerc 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.
- Background: PubMed 22355097Dowling 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.
- Background: PubMed 21054339Kim 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.
- Individual participant dataSharing planned: No. The data is going to be coded, and the relation between data and code are only known by the researches and the IRB (institutional review board).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Adolfo Martinez Tovar, PhD study chair
Hospital General de méxico
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Metformin in people with Acute Lymphoblastic Leukemia, run by Hospital General de Mexico at 1 site in Mexico.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 14 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Daniel Ortiz Morales, MSc (+52 552789200 ext. 2037, dr.ortiz_morales@outlook.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Decrease of ABCB1 gene expression (time frame: The assessment of ABCB1 gene expression will be made at diagnosis (day -7) and at the end of remission induction phase on day +33). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05326984, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Apr 2022.