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Metformin

Extended release Metformin 1500mg once daily for 14-21 days

Adrian Harris

Metformin, a drug that has been used since the 1950's in the treatment of diabetes, has recently generated great interest in its anticancer effects based on in vitro, in vivo and clinical studies. This study assesses the pharmacodynamic effects of metformin on breast cancer metabolism.

The trial design is based on a 2 centre study 'Early Antiangiogenic Response to Bevacizumab in Primary Breast Cancer' that is about to successfully complete recruitment in Oxford and Mount Vernon hospitals. The study takes advantage of the 2 week window between the first clinic visit and commencement of neoadjuvant chemotherapy. Metformin will be given to patients for at least 2 weeks prior to neoadjuvant chemotherapy with a set of 3 breast core biopsies, a PET-CT scan and blood tests carried out before and after this 2 week period of treatment. Patients will also receive a drink of heavy (deuterated) water, a safe and stable isotope commonly used in clinical lipid metabolism studies, the evening prior to both sets of core biopsies. Having completed the first 2 weeks of metformin patients will have the option of continuing metformin until completion of chemotherapy, at the discretion of the trial physician.

The core biopsies will then be used to assess for changes in:

* immunohistochemical staining;
* gene profiles;
* uptake of heavy water into tumour fatty acids using mass spectrometry techniques.

The aim is to identify potential biomarkers of response to metformin (and other future cancer metabolism drugs).

Metformin is a safe and well tolerated drug that has been widely used in the treatment of diabetes for over 50 years. There is now growing evidence from in vitro laboratory and animal work that metformin has anticancer properties. In addition a retrospective clinical study in a diabetic population has demonstrated evidence of markedly increased pathological response rates (a typically robust surrogate clinical endpoint of efficacy) to pre-surgical chemotherapy in early breast cancer for patients that were also taking metformin as part of their diabetes treatment.

There are several studies of metformin in cancer patients ongoing or being developed worldwide These are predominantly in relatively unselected cancer populations and with clinical outcomes as endpoints. However this study is the only study currently planned which will carry out a substantial assessment of pharmacodynamic endpoints. It is important that this study is carried out at an early stage in the development of metformin as a potential cancer therapy in order to ensure that future large scale studies are properly informed.

Effect of Metformin on Breast Cancer Metabolism

A Phase 2 Single Arm Study to Examine the Effects of Metformin on Cancer Metabolism in Patients With Early Stage Breast Cancer Receiving Neoadjuvant Chemotherapy

Cancer Research UK

Oxford University Hospitals NHS Trust

QA Coordinator, Cancer Centre

Blood and Lymph Conditions

Immune System Diseases

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Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

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Acute Lymphoblastic Leukemia

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Antineoplastic Agents

Anti-Infective Agents

Anti-Inflammatory Agents

Etoposide

Cytarabine

Doxorubicin

Liposomal doxorubicin

Prednisone

Vincristine

Etoposide phosphate

Asparaginase

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.

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.

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.

Daniel Ortiz Morales, MSc

Adolfo Martinez Tovar, PhD

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.

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.

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.

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

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).

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

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 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.

The probability of being alive without relapse after randomization of the participants. Will be assess by Kaplan Meir statistics, and compare with log rank.

Hospital General de Mexico

Head of pediatric hematology & oncology

Grith W Højfeldt, BSc

Bente K Pedersen, Professor

The study investigates the explanation for the positive relation found between exercise and breastcancer.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Metformin on Breast Cancer Metabolism	NCT01266486	Breast Cancer	Metformin	18 Years -	Oxford University Hospitals NHS Trust
Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia	NCT05326984	Acute Lymphobla...	Metformin	10 Years - 21 Years	Hospital General de Mexico
Exercise Controls Tumor Cell Growth Through AMPK Activation	NCT01376583	Breast Cancer		18 Years - 30 Years	Rigshospitalet, Denmark
Effect of Metformin on ABCB1 and AMPK Expression in Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia	NCT05326984	Acute Lymphobla...	Metformin	10 Years - 21 Years	Hospital General de Mexico
Effect of Metformin on Breast Cancer Metabolism	NCT01266486	Breast Cancer	Metformin	18 Years -	Oxford University Hospitals NHS Trust

Spots Global Cancer Trial Database for ampk

Every month we try and update this database with for ampk cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for ampk

Every month we try and update this database with for ampk cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for ampk cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.