Rituximab, Cyclophosphamide, Vincristine and Prednisone (R-CHOP) Plus Metformin in Diffuse Large-B-cell Lymphoma

Effect of Metformin in Combination With R-CHOP for the First Line Treatment of Patients With Diffuse Large B-cell Lymphoma

Evaluation of the safety and effectiveness of metformin as an adjunct to RCHOP chemotherapy for patients with newly diagnosed diffuse large-B cell lymphoma

Study Overview

• Status: Completed
• Conditions: Diffuse Large B Cell Lymphoma
• Intervention / Treatment: Drug: Metformin

Detailed Description

Patients with newly diagnosed diffuse large-B cell non Hodgkin lymphoma, irrespective of cell of origin status will receive metformin in combination to Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) chemotherapy for 6 cycles, until response evaluation as reported elsewhere:

1.- Rituximab 375 mg/m2 IV, day 1. 2.- Cyclophosphamide 750 mg/m2 IV, day 1. 3.- Doxorubicin 50 mg/m2 IV day 1. 4.- Vincristine 1.4 mg/m2 IV (2 mg maximum dose). 5.- Prednisone 60 mg/m2 PO days 1-5. Six cycles every 21 days.

Metformin will be added and administered in an outpatient basis, starting with 425 mg twice a day for 1 week, followed by 850 mg twice a day for 1 week, and lastly 850 mg every 8 hours maximum dose until re-staging. Laboratory tests will be performed serially.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mexico
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64610
      • Hospital Universitario Dr. Jose Eleuterio Gonzalez

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with newly diagnosed nodal diffuse large-B cell non Hodgkin lymphoma according to the 2008 World Health Organization classification for lymphoid malignancies
• No previous treatment other than prednisone or equivalent glucocorticoid up to 60 mg/m2 for 14 days
• Good performance status (Eastern Cooperative Oncology Group scale 0-2)
• Life expectancy >6 months
• Independently of the diagnosis of diabetes mellitus (any type)

Exclusion Criteria:

• History of intolerance or hypersensitivity reactions to metformin
• Primary central nervous system lymphoma
• History of other previous malignant neoplastic diseases <5 years prior to enrollment
• Evidence of systemic infection at the time of study
• HIV, hepatitis C or B virus infection
• Aspartate transaminase or alanine transaminase >2x upper limit of normal, bilirubin >2.5 times upper limit of normal
• Serum creatinine >1.5 mg/dL or chronic renal disease
• Cardiac insufficiency (New York Heart Association scale >1 or ejection fraction <50%)
• History of transformation from an indolent lymphoma
• Pregnancy
• History of lactic acidosis or alcoholism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin arm; Metformin 850 mg tablets. Initial dose 425 mg twice a day for 1 week, followed by 850 mg twice a day for 1 week, titrated to a maximum dose 850 mg every 8 hours until disease response evaluation study date (Computed tomography or positron emission tomography)	Drug: Metformin; Potentially increasing the efficacy and safety of standard chemotherapy through several mechanisms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	6 months
Response rates	Overall, partial and complete responses to chemoimmunotherapy	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Survival with freedom from progression	2-5 years
Overall survival	Survival from diagnosis until death or last follow-up	2-5 years
Event-free survival	Survival from diagnosis until death or progression	2-5 years
Time to progression or relapse	Time from diagnosis until disease progression or relapse	2-5 years

Collaborators and Investigators

• Sponsor: Hospital Universitario Dr. Jose E. Gonzalez
• Investigators: Study Chair: David Gómez-Almaguer, MD, Hospital Universitario Dr. Jose Eleuterio Gonzalez

Publications and helpful links

General Publications

• Asensio-Lopez MC, Lax A, Pascual-Figal DA, Valdes M, Sanchez-Mas J. Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system. Free Radic Biol Med. 2011 Nov 15;51(10):1861-71. doi: 10.1016/j.freeradbiomed.2011.08.015. Epub 2011 Aug 25.
• Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, Chen SJ, Chen Y, Zhao WL. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. 2012 Mar 1;3(3):e275. doi: 10.1038/cddis.2012.13.
• Alkhatib Y, Abdel Rahman Z, Kuriakose P. Clinical impact of metformin in diabetic diffuse large B-cell lymphoma patients: a case-control study. Leuk Lymphoma. 2017 May;58(5):1130-1134. doi: 10.1080/10428194.2016.1239822. Epub 2016 Oct 5.

Helpful Links

• Similar study registered in Clinical trials.gov

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2017
• Primary Completion (Actual): August 27, 2018
• Study Completion (Actual): January 27, 2019

Study Registration Dates

• First Submitted: May 24, 2017
• First Submitted That Met QC Criteria: June 25, 2017
• First Posted (Actual): June 27, 2017

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 3, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: HE16-00019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plans for a sharing plan pre-determined

Drug and device information, study documents

• 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