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出境医 / 临床实验 / Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases (OPTIMAL)

Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases (OPTIMAL)

Study Description
Brief Summary:
This is a monocentric, open label, randomized Phase II study in patients with brain metastasis from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three weeks, with or without radiation therapy. The aim is to investigate the metformin efficacy in preventing the onset of glucocorticoid-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer.

Condition or disease Intervention/treatment Phase
Brain Metastases Melanoma Lung Cancer Breast Cancer Drug: Dexamethasone Drug: Metformin Phase 2

Detailed Description:
The study will be conducted in approximately 110 adult patients. aim of the study is to evaluate the effect of oral metformin in preventing GC-induced alterations of systemic metabolism, and in particular GC-induced diabetes. Other clinical objectives of the study consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month. As an exploratory analysis, the effect of dexamethasone plus/minus metformin on other metabolites or growth factors (including amino acids, fatty acids, ketone bodies, IGF-1), as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible patients will be randomized in a 1:1 ratio. Randomization will be stratified by means of minimization technique according to the following factors: primary tumor (melanoma versus lung versus breast cancer), dexamethasone dosage (8-12 mg vs >12 mg daily), baseline (pre-enrollment) fasting glycemia (< 100 versus 100-125 mg/dl). Patients randomized to the experimental arm will discontinue metformin after 30 days, unless diabetes has developed in the meanwhile and the physician believes that metformin is still required for its management. Patients randomized to the control arm who develop steroid-induced diabetes will be prescribed metformin, unless contraindicated, as the preferred therapy option for the management of hyperglycemia. In both treatment arms, dexamethasone will be administered until necessary and at the required dosage in the judgment of the treating physician.
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study
Actual Study Start Date : October 15, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : March 31, 2022
Arms and Interventions
Arm Intervention/treatment
Active Comparator: A (Dexamethasone)
Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route (control arm). The total dose can either administered once a day or through a refracted schedule
 Drug: Dexamethasone
A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.
Experimental: B (Dexamethasone and Metformin)

Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route.The total dose can either administered once a day or through a refracted schedule.

The same patients subjected at a metformin. Metformin initial dosage will be 850 mg per day, and will be escalated based on patient tolerability up to a maximum of 2550 mg daily (experimental arm).

 Drug: Dexamethasone
A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.

Drug: Metformin
A minimum daily dosage of Dexamethasone 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day and 2550 mg daily (maximum dose), oral administration (OS) of Metformin; starting dose will be 850 mg/day, to be progressively increased to 1700 mg/day on day 4 and 2550 mg/day on day 7, if well tolerated.
Other Name: METFORAL
Outcome Measures
Primary Outcome Measures :
  1. Metformin in preventing precocious (14 days) dexamethasone-induced diabetes [ Time Frame: 14 days ]
    To evaluate the efficacy of metformin in preventing precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast cancer.


Secondary Outcome Measures :
  1. Dexamethasone-induced diabetes at 30 days [ Time Frame: 30 days ]
    To study the efficacy of metformin in preventing dexamethasone-induced diabetes at 7 and 30 days after dexamethasone initiation, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast

  2. Short-term mortality [ Time Frame: 90 days ]
    To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone

  3. Brain local control rate of disease [ Time Frame: 30 days ]
    To evaluate the efficacy of metformin in modifying the local disease control rate (brain) in patients treated with radiation therapy (RT) plus dexamethasone at 1 month

  4. Patient ECOG performance status (PS) [ Time Frame: 30 days ]
    To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.

  5. Patient Quality of Life (QoL) [ Time Frame: 30 days ]
    Patient QoL will be evaluated through the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C-30 version 3.0. The EORTC QLQ.C30 instrument will be scored according to the EORTC guidelines.

  6. Absolute counts of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on absolute counts of immune cell populations

  7. Relative counts of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes

  8. Activation status of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on activated antitumor lymphocytes

  9. Plasma lipids profile [ Time Frame: 14 days ]
    To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation

  10. Plasma lipids profile [ Time Frame: 30 days ]
    To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation

  11. Systemic inflammatory parameters [ Time Frame: 2 years ]
    To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)

  12. GC-induced changes in gut microbiota populations [ Time Frame: 30 days ]
    To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)

  13. Metformin-induced changes in gut microbiota populations [ Time Frame: 30 days ]
    To evaluate the impact of metformin on gut microbiota populations (30 days)

  14. Amino acid profile [ Time Frame: 14 days ]
    To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years and ≤ 75 years
  2. Histologically confirmed diagnosis of melanoma, lung (SCLC or NSCLC) or breast cancer
  3. Recent (28 days), radiologically documented (contrast-enhanced CT or MRI) diagnosis of measurable brain metastases requiring treatment with high-dose dexamethasone (at least 8 mg daily for at least 21 days) plus/minus radiation therapy (RT).
  4. Any previous or ongoing antitumor systemic therapy; patients who have never received previous systemic therapy can be also included.
  5. Fasting glycemia < 126 mg/dl at the baseline evaluation or random glycemia of less than 200 mg/dl if the patient has not fasted for at least 8 hours before blood sampling.

  6. Adequate blood tests:

    • Hemoglobin ≥ 9 g/dl
    • Absolute neutrophil count (ANC) in the range between 1.5-10 x 103/μl
    • Total bilirubin ≤ 1.5 times the upper normal limit (UNL). For patients with Gilbert syndrome or known liver metastases, bilirubin levels ≤ 3 times the UNL are considered acceptable
    • AST, ALT ≤ 3 times the UNL
    • Alkaline phosphatase ≤ 2.5 times the UNL
    • Serum creatinine concentration ≤ 1.5 x UNL
  7. ECOG Performance Status ≤ 2
  8. Life expectancy > 6 weeks
  9. Written informed consent
  10. Ability to swallow metformin tablets
  11. Patients of female gender with the potential of childbearing (neither surgically sterile nor 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for at least 60 days after study conclusion. Acceptable methods of contraception include double barrier method [i.e. condom and occlusive cap (diaphragm or cervical vault caps)] spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method.
  12. Patients of male gender having female partners with childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 60 days after participation in the study

Exclusion Criteria:

  1. Leptomeningeal carcinomatosis, either radiologically documented or cytologically confirmed
  2. History of brain metastases
  3. Diagnosis of other malignancies in the last 5 years, except for superficial, radically treated basal cell carcinomas of the skin or in situ carcinomas of the cervix
  4. Previous or current use of metformin
  5. Ongoing therapy with systemic glucocorticoids at a dosage that is higher than 10 mg prednisone equivalent. Previous GC treatment is allowed if stopped at least 2 months before enrollment. Inhaled or topical steroids are permitted.
  6. Diagnosis of Type 1 or Type 2 diabetes mellitus
  7. Known history of HBV- or HCV-related infection
  8. Known liver cirrhosis, even in the absence of significant alterations in blood tests
  9. Clinically uncontrolled disorders of the lung, kidney, liver or cardio-vascular apparatus
  10. Known history of HIV infection
  11. Serious neurological or psychiatric disorders
  12. Absence of a caregiver for patients with an ECOG performance status of 2
  13. Pregnancy or lactation
  14. Body mass index < 18.5 kg/m2
  15. Past or current alcohol abuse (> 36 grams/day for men and 24grams/day for women)
  16. Documented metabolic acidosis from any cause in the last 5 years
  17. History of allergy or hypersensitivity to study drug components
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Filippo De Braud, Professor 0039 02 23902148 Filippo.DeBraud@istitutotumori.mi.it
Contact: Claudio Vernieri, MD 0039 02 23903066 Claudio.Vernieri@istitutotumori.mi.it

Locations
Layout table for location information
Italy
Fondazione IRCCS Istituto Nazionale dei Tumori Recruiting
Milan, Italy, 20133
Contact: Claudio Vernieri, M.D., Ph.D.    +39 02 23903066    claudio.vernieri@istitutotumori.mi.it   
Sponsors and Collaborators
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
University of Milan
Investigators
Layout table for investigator information
Principal Investigator: Filippo De Braud, Professor Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Tracking Information
First Submitted Date  ICMJE June 4, 2019
First Posted Date  ICMJE June 28, 2019
Last Update Posted Date November 13, 2019
Actual Study Start Date  ICMJE October 15, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2019) 		Metformin in preventing precocious (14 days) dexamethasone-induced diabetes [ Time Frame: 14 days ]
To evaluate the efficacy of metformin in preventing precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast cancer.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2019)
  • Dexamethasone-induced diabetes at 30 days [ Time Frame: 30 days ]
    To study the efficacy of metformin in preventing dexamethasone-induced diabetes at 7 and 30 days after dexamethasone initiation, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast
  • Short-term mortality [ Time Frame: 90 days ]
    To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone
  • Brain local control rate of disease [ Time Frame: 30 days ]
    To evaluate the efficacy of metformin in modifying the local disease control rate (brain) in patients treated with radiation therapy (RT) plus dexamethasone at 1 month
  • Patient ECOG performance status (PS) [ Time Frame: 30 days ]
    To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.
  • Patient Quality of Life (QoL) [ Time Frame: 30 days ]
    Patient QoL will be evaluated through the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C-30 version 3.0. The EORTC QLQ.C30 instrument will be scored according to the EORTC guidelines.
  • Absolute counts of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on absolute counts of immune cell populations
  • Relative counts of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes
  • Activation status of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on activated antitumor lymphocytes
  • Plasma lipids profile [ Time Frame: 14 days ]
    To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation
  • Plasma lipids profile [ Time Frame: 30 days ]
    To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation
  • Systemic inflammatory parameters [ Time Frame: 2 years ]
    To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)
  • GC-induced changes in gut microbiota populations [ Time Frame: 30 days ]
    To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)
  • Metformin-induced changes in gut microbiota populations [ Time Frame: 30 days ]
    To evaluate the impact of metformin on gut microbiota populations (30 days)
  • Amino acid profile [ Time Frame: 14 days ]
    To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • Dexamethasone-induced diabetes at 30 days [ Time Frame: 30 days ]
    To study the efficacy of metformin in preventing dexamethasone-induced diabetes at 7 and 30 days after dexamethasone initiation, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast
  • Short-term mortality [ Time Frame: 90 days ]
    To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone
  • Brain local control rate of disease [ Time Frame: 30 days ]
    To evaluate the efficacy of metformin in modifying the local disease control rate (brain) in patients treated with radiation therapy (RT) plus dexamethasone at 1 month
  • Patient ECOG performance status (PS) [ Time Frame: 30 days ]
    To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.
  • Patient Quality of Life (QoL) [ Time Frame: 30 days ]
    Patient QoL will be evaluated through the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C-30 version 3.0. The EORTC QLQ.C30 instrument will be scored according to the EORTC guidelines.
  • Absolute counts of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on absolute counts of immune cell populations
  • Relative counts of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes
  • Activation status of immune cell populations [ Time Frame: 2 years ]
    To investigate the potential impact of metformin on activated antitumor lymphocytes
  • Plasma lipids profile [ Time Frame: 14 days ]
    To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation
  • Plasma lipids profile [ Time Frame: 30 days ]
    To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation
  • Systemic inflammatory parameters [ Time Frame: 2 years ]
    To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)
  • GC-induced changes in gut microbiota populations [ Time Frame: 30 days ]
    To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)
  • Metformin-induced changes in gut microbiota populations [ Time Frame: 30 days ]
    To evaluate the impact of metformin on gut microbiota populations (30 days)
  • Amino acid profile [ Time Frame: 30 days ]
    To study the effect of metformin in modifying the plasma amino acid profile at 7, 14 and 30 days after treatment initiation
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases
Official Title  ICMJE Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study
Brief Summary This is a monocentric, open label, randomized Phase II study in patients with brain metastasis from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three weeks, with or without radiation therapy. The aim is to investigate the metformin efficacy in preventing the onset of glucocorticoid-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer.
Detailed Description The study will be conducted in approximately 110 adult patients. aim of the study is to evaluate the effect of oral metformin in preventing GC-induced alterations of systemic metabolism, and in particular GC-induced diabetes. Other clinical objectives of the study consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month. As an exploratory analysis, the effect of dexamethasone plus/minus metformin on other metabolites or growth factors (including amino acids, fatty acids, ketone bodies, IGF-1), as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Eligible patients will be randomized in a 1:1 ratio. Randomization will be stratified by means of minimization technique according to the following factors: primary tumor (melanoma versus lung versus breast cancer), dexamethasone dosage (8-12 mg vs >12 mg daily), baseline (pre-enrollment) fasting glycemia (< 100 versus 100-125 mg/dl). Patients randomized to the experimental arm will discontinue metformin after 30 days, unless diabetes has developed in the meanwhile and the physician believes that metformin is still required for its management. Patients randomized to the control arm who develop steroid-induced diabetes will be prescribed metformin, unless contraindicated, as the preferred therapy option for the management of hyperglycemia. In both treatment arms, dexamethasone will be administered until necessary and at the required dosage in the judgment of the treating physician.
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Brain Metastases
  • Melanoma
  • Lung Cancer
  • Breast Cancer
Intervention  ICMJE
  • Drug: Dexamethasone
    A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.
  • Drug: Metformin
    A minimum daily dosage of Dexamethasone 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day and 2550 mg daily (maximum dose), oral administration (OS) of Metformin; starting dose will be 850 mg/day, to be progressively increased to 1700 mg/day on day 4 and 2550 mg/day on day 7, if well tolerated.
    Other Name: METFORAL
Study Arms  ICMJE
  • Active Comparator: A (Dexamethasone)
    Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route (control arm). The total dose can either administered once a day or through a refracted schedule
    Intervention: Drug: Dexamethasone
  • Experimental: B (Dexamethasone and Metformin)

    Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route.The total dose can either administered once a day or through a refracted schedule.

    The same patients subjected at a metformin. Metformin initial dosage will be 850 mg per day, and will be escalated based on patient tolerability up to a maximum of 2550 mg daily (experimental arm).

    Interventions:
    • Drug: Dexamethasone
    • Drug: Metformin
Publications *
  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. Review.
  • Vernieri C, Casola S, Foiani M, Pietrantonio F, de Braud F, Longo V. Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions. Cancer Discov. 2016 Dec;6(12):1315-1333. Epub 2016 Nov 21. Review.
  • O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016 Sep;16(9):553-65. doi: 10.1038/nri.2016.70. Epub 2016 Jul 11. Review.
  • Lin X, DeAngelis LM. Treatment of Brain Metastases. J Clin Oncol. 2015 Oct 20;33(30):3475-84. doi: 10.1200/JCO.2015.60.9503. Epub 2015 Aug 17. Review.
  • Harris D, Barts A, Connors J, Dahl M, Elliott T, Kong J, Keane T, Thompson D, Stafford S, Ur E, Sirrs S. Glucocorticoid-induced hyperglycemia is prevalent and unpredictable for patients undergoing cancer therapy: an observational cohort study. Curr Oncol. 2013 Dec;20(6):e532-8. doi: 10.3747/co.20.1499.
  • Weiser MA, Cabanillas ME, Konopleva M, Thomas DA, Pierce SA, Escalante CP, Kantarjian HM, O'Brien SM. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer. 2004 Mar 15;100(6):1179-85.
  • Furnary AP, Gao G, Grunkemeier GL, Wu Y, Zerr KJ, Bookin SO, Floten HS, Starr A. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003 May;125(5):1007-21.
  • Perez A, Jansen-Chaparro S, Saigi I, Bernal-Lopez MR, Miñambres I, Gomez-Huelgas R. Glucocorticoid-induced hyperglycemia. J Diabetes. 2014 Jan;6(1):9-20. doi: 10.1111/1753-0407.12090. Epub 2013 Oct 29. Review.
  • Oyer DS, Shah A, Bettenhausen S. How to manage steroid diabetes in the patient with cancer. J Support Oncol. 2006 Oct;4(9):479-83. Review.
  • Bozzi F, Mogavero A, Varinelli L, Belfiore A, Manenti G, Caccia C, Volpi CC, Beznoussenko GV, Milione M, Leoni V, Gloghini A, Mironov AA, Leo E, Pilotti S, Pierotti MA, Bongarzone I, Gariboldi M. MIF/CD74 axis is a target for novel therapies in colon carcinomatosis. J Exp Clin Cancer Res. 2017 Jan 23;36(1):16. doi: 10.1186/s13046-016-0475-z.
  • Wallace MD, Metzger NL. Optimizing the Treatment of Steroid-Induced Hyperglycemia. Ann Pharmacother. 2018 Jan;52(1):86-90. doi: 10.1177/1060028017728297. Epub 2017 Aug 24. Review.
  • Kwon S, Hermayer KL, Hermayer K. Glucocorticoid-induced hyperglycemia. Am J Med Sci. 2013 Apr;345(4):274-277. doi: 10.1097/MAJ.0b013e31828a6a01. Review.
  • Zhang ZJ, Bi Y, Li S, Zhang Q, Zhao G, Guo Y, Song Q. Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis. Am J Epidemiol. 2014 Jul 1;180(1):11-4. doi: 10.1093/aje/kwu124. Epub 2014 Jun 10. Review.
  • Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010 Jun;33(6):1304-8. doi: 10.2337/dc09-1791. Epub 2010 Mar 18.
  • Pusceddu S, Vernieri C, Di Maio M, Marconcini R, Spada F, Massironi S, Ibrahim T, Brizzi MP, Campana D, Faggiano A, Giuffrida D, Rinzivillo M, Cingarlini S, Aroldi F, Antonuzzo L, Berardi R, Catena L, De Divitiis C, Ermacora P, Perfetti V, Fontana A, Razzore P, Carnaghi C, Davì MV, Cauchi C, Duro M, Ricci S, Fazio N, Cavalcoli F, Bongiovanni A, La Salvia A, Brighi N, Colao A, Puliafito I, Panzuto F, Ortolani S, Zaniboni A, Di Costanzo F, Torniai M, Bajetta E, Tafuto S, Garattini SK, Femia D, Prinzi N, Concas L, Lo Russo G, Milione M, Giacomelli L, Buzzoni R, Delle Fave G, Mazzaferro V, de Braud F. Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues. Gastroenterology. 2018 Aug;155(2):479-489.e7. doi: 10.1053/j.gastro.2018.04.010. Epub 2018 Apr 13.
  • Seelig E, Meyer S, Timper K, Nigro N, Bally M, Pernicova I, Schuetz P, Müller B, Korbonits M, Christ-Crain M. Metformin prevents metabolic side effects during systemic glucocorticoid treatment. Eur J Endocrinol. 2017 Mar;176(3):349-358. doi: 10.1530/EJE-16-0653. Epub 2017 Jan 10.
  • Bostrom B, Uppal P, Chu J, Messinger Y, Gandrud L, McEvoy R. Safety and efficacy of metformin for therapy-induced hyperglycemia in children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2013 Oct;35(7):504-8. doi: 10.1097/MPH.0b013e31829cdeba.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 26, 2019) 		110
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age ≥ 18 years and ≤ 75 years
  2. Histologically confirmed diagnosis of melanoma, lung (SCLC or NSCLC) or breast cancer
  3. Recent (28 days), radiologically documented (contrast-enhanced CT or MRI) diagnosis of measurable brain metastases requiring treatment with high-dose dexamethasone (at least 8 mg daily for at least 21 days) plus/minus radiation therapy (RT).
  4. Any previous or ongoing antitumor systemic therapy; patients who have never received previous systemic therapy can be also included.
  5. Fasting glycemia < 126 mg/dl at the baseline evaluation or random glycemia of less than 200 mg/dl if the patient has not fasted for at least 8 hours before blood sampling.

  6. Adequate blood tests:

    • Hemoglobin ≥ 9 g/dl
    • Absolute neutrophil count (ANC) in the range between 1.5-10 x 103/μl
    • Total bilirubin ≤ 1.5 times the upper normal limit (UNL). For patients with Gilbert syndrome or known liver metastases, bilirubin levels ≤ 3 times the UNL are considered acceptable
    • AST, ALT ≤ 3 times the UNL
    • Alkaline phosphatase ≤ 2.5 times the UNL
    • Serum creatinine concentration ≤ 1.5 x UNL
  7. ECOG Performance Status ≤ 2
  8. Life expectancy > 6 weeks
  9. Written informed consent
  10. Ability to swallow metformin tablets
  11. Patients of female gender with the potential of childbearing (neither surgically sterile nor 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for at least 60 days after study conclusion. Acceptable methods of contraception include double barrier method [i.e. condom and occlusive cap (diaphragm or cervical vault caps)] spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method.
  12. Patients of male gender having female partners with childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 60 days after participation in the study

Exclusion Criteria:

  1. Leptomeningeal carcinomatosis, either radiologically documented or cytologically confirmed
  2. History of brain metastases
  3. Diagnosis of other malignancies in the last 5 years, except for superficial, radically treated basal cell carcinomas of the skin or in situ carcinomas of the cervix
  4. Previous or current use of metformin
  5. Ongoing therapy with systemic glucocorticoids at a dosage that is higher than 10 mg prednisone equivalent. Previous GC treatment is allowed if stopped at least 2 months before enrollment. Inhaled or topical steroids are permitted.
  6. Diagnosis of Type 1 or Type 2 diabetes mellitus
  7. Known history of HBV- or HCV-related infection
  8. Known liver cirrhosis, even in the absence of significant alterations in blood tests
  9. Clinically uncontrolled disorders of the lung, kidney, liver or cardio-vascular apparatus
  10. Known history of HIV infection
  11. Serious neurological or psychiatric disorders
  12. Absence of a caregiver for patients with an ECOG performance status of 2
  13. Pregnancy or lactation
  14. Body mass index < 18.5 kg/m2
  15. Past or current alcohol abuse (> 36 grams/day for men and 24grams/day for women)
  16. Documented metabolic acidosis from any cause in the last 5 years
  17. History of allergy or hypersensitivity to study drug components
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Filippo De Braud, Professor 0039 02 23902148 Filippo.DeBraud@istitutotumori.mi.it
Contact: Claudio Vernieri, MD 0039 02 23903066 Claudio.Vernieri@istitutotumori.mi.it
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04001725
Other Study ID Numbers  ICMJE INT31/19
B43C17000350001 ( Other Grant/Funding Number: Italian Minister of Health (5x1000 year 2014) )
2019-000105-73 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Filippo de Braud, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study Sponsor  ICMJE Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Collaborators  ICMJE University of Milan
Investigators  ICMJE
Principal Investigator: Filippo De Braud, Professor Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
PRS Account Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

治疗医院

新药特效药

治疗案例

前沿医讯