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

Breast Cancer Clinical Trial

— OPTIMAL  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04001725
• Other study ID #: INT31/19
• Secondary ID: B43C170003500012
• Status: Recruiting
• Phase: Phase 2
• Start date: October 15, 2019
• Est. completion date: March 31, 2022

Study information

• Verified date: November 2019
• Source: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Contact: Filippo De Braud, Professor
• Phone: 0039 02 23902148
• Email: Filippo.DeBraud[@]istitutotumori.mi.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: March 31, 2022
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Metastases
• Brain Neoplasms
• Breast Cancer
• Lung Cancer
• Lung Neoplasms
• Melanoma
• Neoplasm Metastasis

Intervention

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

Locations

Country	Name	City	State
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milan

Sponsors (2)

Lead Sponsor	Collaborator
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano	University of Milan

Country where clinical trial is conducted

Italy, 

References & Publications (17)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Metformin in preventing precocious (14 days) dexamethasone-induced diabetes	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.	14 days
Secondary	Dexamethasone-induced diabetes at 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	30 days
Secondary	Short-term mortality	To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone	90 days
Secondary	Brain local control rate of disease	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	30 days
Secondary	Patient ECOG performance status (PS)	To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.	30 days
Secondary	Patient Quality of Life (QoL)	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.	30 days
Secondary	Absolute counts of immune cell populations	To investigate the potential impact of metformin on absolute counts of immune cell populations	2 years
Secondary	Relative counts of immune cell populations	To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes	2 years
Secondary	Activation status of immune cell populations	To investigate the potential impact of metformin on activated antitumor lymphocytes	2 years
Secondary	Plasma lipids profile	To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation	14 days
Secondary	Plasma lipids profile	To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation	30 days
Secondary	Systemic inflammatory parameters	To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)	2 years
Secondary	GC-induced changes in gut microbiota populations	To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)	30 days
Secondary	Metformin-induced changes in gut microbiota populations	To evaluate the impact of metformin on gut microbiota populations (30 days)	30 days
Secondary	Amino acid profile	To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation	14 days