Acute Lymphoblastic LeukemiaNCT03118128
Metformin Reduce the Relapse Rate on Patients With B-cell Precursor (Ph+ Negative) Acute Lymphoblastic Leukemia
A study testing Metformin in people with Acute Lymphoblastic Leukemia, run by Hospital General de Mexico.
Trial summary
Metformin's Antitumor activity were identified from differens diabetic patients trials, mainly associated to its mechanism of action and protein - kinase AMPK (AMP-activated protein kinase) activation. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Acute Lymphoblastic Leukemia
- What is being tested?
- Metformin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 102 participants
- Where
- No sites listed yet
- Study dates
- 1 Jan 2015to 30 Apr 2017
- 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 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- > 18 years
- de novo B-cell precursor Acute Lymphoblastic Leukemia
- candidates to first line treatment protocol
- ECOG (Eastern Cooperative Oncology Group) Scale of Performance Status 1/2
- Informed Consent Form for genetic analysis samples
- Precursor B Cell Acute Lymphoblastic Leukemia
Who cannot join
- Diagnose of Acute Myelogenous Leukemia or Biphenotype Leukemia
- Diagnose of type 2 Diabetes Mellitus
- Previous use of Metformin
- Relapsed Acute Leukemia that require treatment protocol to be started
- Intolerance to prednisone
- ECOG Scale of Performance Status 3/4
Show all 15Show fewer
- T-cell Acute Lymphoblastic Leukemia
- Philadelphia positive Acute Lymphoblastic Leukemia
- Tumor lysis syndrome at diagnose
- Renal Failure (creatinine leve higher than 2mg/dl)
- Several liver damage (>2 levels de upper normal limit of Aspartate transaminase (AST) and alanine transaminase (ALT)
- Metabolic Acidosis or Lactic Acidosis at diagnose
- Central nervous system infiltration at diagnose
- Extramedullary disease (skin, pleura,eye)
- Active GI bleeding
About this study
Official title: Effect of the Addition of Metformin Hydrochloride on the Prognosis of Patients With B-cell Precursor (Ph+ Negative) Acute Lymphoblastic Leukemia With High Expression of ABCB1 Gene
Metformin's Antitumor activity were identified from differens diabetic patients trials, mainly associated to its mechanism of action and protein - kinase AMPK (AMP-activated protein kinase) activation. According to Cancer and Diabetes International Consensus from 2012, diabetes increases the risk for developping cancer and metformin has an protector effect against cancer cells and has an impact on overall survival.
Chemotherapy drug resistance induces treatment fail in oncology. Metformin increases AMPK levels, blocks PI3K (phosphatidylinositol 3- kinase)/ AKT /mTOR(mammailian Target of Rapamycin) pathway but few evidence associated with drug resistance gene expression.
This is an, experimental one-center study that pretends to stablish the effect of adding metformin 850 mg PO three times a day over the multi-drug resistance gene expression (ABCB1) in de novo Acute Lymphoblastic Leukemia in one 7-days cycle with prednisone as pre-treatment- and on the induction remission treatment.
Read the detailed description
The MDR (Multidrug-Resistance) Genes are implicated on the resistance of several types of cancer. The most important on leukemia are the ABCB1 and ABCG2- ABCB1 are implicated on resistance and severity on Acute Myeloid Leukemia and pediatric Acute Lymphoblastic Leukemia. Those transporters use ATP for use. Metformin decrease the intracellular ATP (Adenosine triphosphate) reserve the by the activation of AMPK. Recently on MCF7-Adr (Michigan Cancer Foundation 7, breast cancer cell line) cancer cell line, Metformin block the function of the P-glycoprotein by the inhibition of the Nuclear Factor -kappa-B.
The clinical evidence at this moment is limited, based on small clinical trials or observational studies. This study tries to evaluate the effect of the addition of Metformin to a standard chemotherapy regimen on patients who express high levels of expression of mRNA (messenger ribonucleic acid) ABCB1
Experimental protocol
The patients will be stratified on three groups: The high-expression, low expression and absent gene expression according the level mRNA of ABCB1 at diagnostic. The samples are obtained from mononuclear peripheral blood cells
Extraction of total RNA Total RNA was isolated by TRIzol® (Invtirogen Life Technologies) according to the manufacturer´s recomendations described by Chomczynski and Sacchi.
The concentration and purity of total RNA was determined in a UV -vis spectrophotometer (Thermo Scientific , Genesis 10S UV-vis). The integrity of the genetic material was confirmed by 1.5% agarose gel electrophoresis at 70 V for 40 min. The RNA was stored at -80°C until needed.
Synthesis of cDNA Fort he synthesis of c DNA (complementary deoxyribonucleic acid) the amount of RNA used was 2µg for a final volume of 20 µg. The RNA was mixed with 1 µl oligonucleotide 12-18 (INVITROGEN, Carlsbad, CA) and 1 µl de dNTPs (deoxynucleoside triphosphate) 10mM (Applied Biosystems, Roche). After the addition of 4 µl of Buffer 5 X (Tris- HCl (hydrochloric acid) 250mM, KCl (potassium chloride) 375 mM MgCl2 15mM), 2 µl de DTT (dithiothreitol) (0.1M) and wáter, all the mix was incubated at at 37° for two minutes and 1 µl of MMLV(Moloney Murine Leukemia Virus Reverse Transcriptase) Reverse transcriptase- enzyme (200u) (INVITROGEN, Carlsbad, CA) and incubated at 37°C for 50 minutes.
Real-time polymerase chain reaction (qRT-PCR) analysis The mRNA expression levels of the ABCB1 (Hs01069047), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; Hs00985689) genes were measured using the TaqMan® gene expression assay (Applied Biosystems, Foster City, CA, USA). The GAPDH gene was used as an endogenous control, and each sample was analyzed in triplicate. The relative expression levels were calculated using the 2-ΔΔCtmethod with bone marrow as a calibrator. The high and low expression cut-off points were determined by the mean values observed in healthy donors.
Treatment protocol All the patients recieve an induction remission treatment with an initial pre-induction phase with steroids (prednisone) from day -7 to day -1 (-7 ,-6 = 25mg , -5 , -4 : 50mg , -3, -2: 75mg and on day -1 : 100mg). The induction remission treatment is based on a 28 day treatment with prednisone (60mg/m2),Vincristine (1.5mg/m2 maxium 2mg) and Daunorubicin 60mg/m2 on days +1, +8 and +15. If the patient archive a Complete Remission, continues with a consolidation therapy with sequential blocks of treatment that includes Cytarabine, Etoposide, Methotrexate. If the patient still on remission at the end of consolidation therapy continues on maintenance phase that includes 6-mercaptopurine and a weekly dose of methotrexate for around two years
Response At day 28 of the induction remission treatment, according the result of bone marrow sample the patientes will be declared on remission (less than 5% blast) or refractory (>5% blast cell). If the patient present at any point of treatment an increase on bone marrow blast count the patient is considered on relapse.
- Conditions
- Acute Lymphoblastic Leukemia
- Being tested
- Metformin
- Keywords
- Acute Lymphoblastic Leukemia (ALL), ABCB1, Metformin
- 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 850 mg PO three times a day plus prednisone in one 7-days cycle as pre-treatment and during the 28 days induction remission treatment, consolidation therapy and maintenance
| Study group | Role | What they receive |
|---|---|---|
| metformin | Active comparator | Metformin 850mg PO three times a day, during the pre-induction with steroids, induction remission, consolidation and maintenance Receives: Drug: Metformin |
| No metformin | No intervention | Not described |
What is being measured
The primary outcome is the main question the study is designed to answer.
Effect of Metformin on first line treatment Refractoriness in high risk failure ALL patients
Effect on the refractoriness frequency in high risk failure patients (High levels of ABCB1)
Measured: 28 day induction remission treatment
Effect of Metformin on relapse rate and survival of high risk failure ALL patients
Effect of Metformin on Relapse Free Survival (RFS) on patients with high risk failure (high levels of ABCB1 gene )
Measured: 12 months of follow up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2017
- Study start1 Jan 2015
- Primary completion1 Dec 2016
- Study completion30 Apr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)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
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 102 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hospital General de Mexico
- Sponsor type
- Other government
- Responsible party
- Principal investigator, Christian Ramos Penafiel, Hospital General de Mexico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03118128
- Sponsor's protocol ID
- HGM-CRP2-LLA
- Status last verified
- Apr 2017
- First submitted
- 7 Apr 2017
- Last updated
- 6 Jul 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 21054339Olarte Carrillo I, Ramos Penafiel C, Miranda Peralta E, Rozen Fuller E, Kassack Ipina JJ, Centeno Cruz F, Garrido Guerrero E, Collazo Jaloma J, Nacho Vargas K, Martinez Tovar A. Clinical significance of the ABCB1 and ABCG2 gene expression levels in acute lymphoblastic leukemia. Hematology. 2017 Jun;22(5):286-291. doi: 10.1080/10245332.2016.1265780. Epub 2016 Dec 14.
PubMed 27960630Ramos-Penafiel C, Olarte-Carrillo I, Ceron-Maldonado R, Rozen-Fuller E, Kassack-Ipina JJ, Melendez-Mier G, Collazo-Jaloma J, Martinez-Tovar A. Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene. J Transl Med. 2018 Sep 3;16(1):245. doi: 10.1186/s12967-018-1620-6.
PubMed 30176891
Study at a glance
From the registry record, last updated by the sponsor on 6 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of the Addition of Metformin Hydrochloride on the Prognosis of Patients With B-cell Precursor (Ph+ Negative) Acute Lymphoblastic Leukemia With High Expression of ABCB1 Gene
- ClinicalTrials.gov ID
- NCT03118128
- Acronym / sponsor ID
- HGM-CRP2-LLA
- Conditions
- Acute Lymphoblastic Leukemia
- Keywords
- Acute Lymphoblastic Leukemia (ALL), ABCB1, Metformin
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 102 participants (actual)
- Lead sponsor
- Hospital General de MexicoOther government
- Study start
- 1 Jan 2015 (actual)
- Primary completion
- 1 Dec 2016 (actual)
- Study completion
- 30 Apr 2017 (actual)
- First posted
- 18 Apr 2017 (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.
Metformin's Antitumor activity were identified from differens diabetic patients trials, mainly associated to its mechanism of action and protein - kinase AMPK (AMP-activated protein kinase) activation. According to Cancer and Diabetes International Consensus from 2012, diabetes increases the risk for developping cancer and metformin has an protector effect against cancer cells and has an impact on overall survival.
Chemotherapy drug resistance induces treatment fail in oncology. Metformin increases AMPK levels, blocks PI3K (phosphatidylinositol 3- kinase)/ AKT /mTOR(mammailian Target of Rapamycin) pathway but few evidence associated with drug resistance gene expression.
This is an, experimental one-center study that pretends to stablish the effect of adding metformin 850 mg PO three times a day over the multi-drug resistance gene expression (ABCB1) in de novo Acute Lymphoblastic Leukemia in one 7-days cycle with prednisone as pre-treatment- and on the induction remission treatment.
Detailed description
The MDR (Multidrug-Resistance) Genes are implicated on the resistance of several types of cancer. The most important on leukemia are the ABCB1 and ABCG2- ABCB1 are implicated on resistance and severity on Acute Myeloid Leukemia and pediatric Acute Lymphoblastic Leukemia. Those transporters use ATP for use. Metformin decrease the intracellular ATP (Adenosine triphosphate) reserve the by the activation of AMPK. Recently on MCF7-Adr (Michigan Cancer Foundation 7, breast cancer cell line) cancer cell line, Metformin block the function of the P-glycoprotein by the inhibition of the Nuclear Factor -kappa-B.
The clinical evidence at this moment is limited, based on small clinical trials or observational studies. This study tries to evaluate the effect of the addition of Metformin to a standard chemotherapy regimen on patients who express high levels of expression of mRNA (messenger ribonucleic acid) ABCB1
Experimental protocol
The patients will be stratified on three groups: The high-expression, low expression and absent gene expression according the level mRNA of ABCB1 at diagnostic. The samples are obtained from mononuclear peripheral blood cells
Extraction of total RNA Total RNA was isolated by TRIzol® (Invtirogen Life Technologies) according to the manufacturer´s recomendations described by Chomczynski and Sacchi.
The concentration and purity of total RNA was determined in a UV -vis spectrophotometer (Thermo Scientific , Genesis 10S UV-vis). The integrity of the genetic material was confirmed by 1.5% agarose gel electrophoresis at 70 V for 40 min. The RNA was stored at -80°C until needed.
Synthesis of cDNA Fort he synthesis of c DNA (complementary deoxyribonucleic acid) the amount of RNA used was 2µg for a final volume of 20 µg. The RNA was mixed with 1 µl oligonucleotide 12-18 (INVITROGEN, Carlsbad, CA) and 1 µl de dNTPs (deoxynucleoside triphosphate) 10mM (Applied Biosystems, Roche). After the addition of 4 µl of Buffer 5 X (Tris- HCl (hydrochloric acid) 250mM, KCl (potassium chloride) 375 mM MgCl2 15mM), 2 µl de DTT (dithiothreitol) (0.1M) and wáter, all the mix was incubated at at 37° for two minutes and 1 µl of MMLV(Moloney Murine Leukemia Virus Reverse Transcriptase) Reverse transcriptase- enzyme (200u) (INVITROGEN, Carlsbad, CA) and incubated at 37°C for 50 minutes.
Real-time polymerase chain reaction (qRT-PCR) analysis The mRNA expression levels of the ABCB1 (Hs01069047), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH; Hs00985689) genes were measured using the TaqMan® gene expression assay (Applied Biosystems, Foster City, CA, USA). The GAPDH gene was used as an endogenous control, and each sample was analyzed in triplicate. The relative expression levels were calculated using the 2-ΔΔCtmethod with bone marrow as a calibrator. The high and low expression cut-off points were determined by the mean values observed in healthy donors.
Treatment protocol All the patients recieve an induction remission treatment with an initial pre-induction phase with steroids (prednisone) from day -7 to day -1 (-7 ,-6 = 25mg , -5 , -4 : 50mg , -3, -2: 75mg and on day -1 : 100mg). The induction remission treatment is based on a 28 day treatment with prednisone (60mg/m2),Vincristine (1.5mg/m2 maxium 2mg) and Daunorubicin 60mg/m2 on days +1, +8 and +15. If the patient archive a Complete Remission, continues with a consolidation therapy with sequential blocks of treatment that includes Cytarabine, Etoposide, Methotrexate. If the patient still on remission at the end of consolidation therapy continues on maintenance phase that includes 6-mercaptopurine and a weekly dose of methotrexate for around two years
Response At day 28 of the induction remission treatment, according the result of bone marrow sample the patientes will be declared on remission (less than 5% blast) or refractory (>5% blast cell). If the patient present at any point of treatment an increase on bone marrow blast count the patient is considered on relapse.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| metformin | Active comparator | Drug: MetforminMetformin 850mg PO three times a day, during the pre-induction with steroids, induction remission, consolidation and maintenance |
| No metformin | No intervention | – |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- > 18 years
- de novo B-cell precursor Acute Lymphoblastic Leukemia
- candidates to first line treatment protocol
- ECOG (Eastern Cooperative Oncology Group) Scale of Performance Status 1/2
- Informed Consent Form for genetic analysis samples
Key exclusion criteria (15 listed)
- Diagnose of Acute Myelogenous Leukemia or Biphenotype Leukemia
- Diagnose of type 2 Diabetes Mellitus
- Previous use of Metformin
- Relapsed Acute Leukemia that require treatment protocol to be started
- Intolerance to prednisone
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 850 mg PO three times a day plus prednisone in one 7-days cycle as pre-treatment and during the 28 days induction remission treatment, consolidation therapy and maintenance | Drug | metformin |
Primary outcome
Effect of Metformin on first line treatment Refractoriness in high risk failure ALL patients
Time frame: 28 day induction remission treatment
Effect on the refractoriness frequency in high risk failure patients (High levels of ABCB1)
Effect of Metformin on relapse rate and survival of high risk failure ALL patients
Time frame: 12 months of follow up
Effect of Metformin on Relapse Free Survival (RFS) on patients with high risk failure (high levels of ABCB1 gene )
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Jul 2017.
- 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.
- Background: PubMed 27960630Olarte Carrillo I, Ramos Penafiel C, Miranda Peralta E, Rozen Fuller E, Kassack Ipina JJ, Centeno Cruz F, Garrido Guerrero E, Collazo Jaloma J, Nacho Vargas K, Martinez Tovar A. Clinical significance of the ABCB1 and ABCG2 gene expression levels in acute lymphoblastic leukemia. Hematology. 2017 Jun;22(5):286-291. doi: 10.1080/10245332.2016.1265780. Epub 2016 Dec 14.
- Derived from this study: PubMed 30176891Ramos-Penafiel C, Olarte-Carrillo I, Ceron-Maldonado R, Rozen-Fuller E, Kassack-Ipina JJ, Melendez-Mier G, Collazo-Jaloma J, Martinez-Tovar A. Effect of metformin on the survival of patients with ALL who express high levels of the ABCB1 drug resistance gene. J Transl Med. 2018 Sep 3;16(1):245. doi: 10.1186/s12967-018-1620-6.
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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.
The record lists no contact. Use the official record to reach the sponsor.
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.
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 6 inclusion and 15 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: finished, as of the sponsor's last update on 6 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effect of Metformin on first line treatment Refractoriness in high risk failure ALL patients (time frame: 28 day induction remission treatment). 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 NCT03118128, which also lists 3 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 6 Jul 2017.