Clinical Activity of Metformin With High-dose of Dexamethasone in Relapse Multiple Myeloma

NCT02967276 | Unknown Phase 2

• 1 other identifier: METDEXA-MM
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 2

Brief Summary

This phase II trial study assessing the activity of metformin when given together with high dose of dexamethasone in treating patients with multiple myeloma (MM) that has relapse or refractory to previous treatment. High dose of dexamethasone (HDdexa) is used to treat relapse/refractary patients with myeloma and metformin also demonstrated synergistic activity with dexamethasone to eradicate MM cells in vitro and in vivo. Metformin hydrochloride, used for diabetes, may also help kill tumor cells. Giving dexamethasone with metformin may kill more MM cells and increase the response rate to HDdexa.

Conditions

Multiple Myeloma

Keywords

Metformin; Dexamethasone; Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• Response Rate (RR)

  the RR to metformin and HDdexa schedule including: complete (CR), partial (PR) and minimal (MR) response in patients with relapsed/refractory multiple myeloma criteria for defining response according to the International Myeloma Working Group (IMWG): CR: Negative immunofixation of serum and urine, and Disappearance of any soft tissue plasmacytomas, and below of 5% Plasma Cells in bone marrow. PR: above or equal 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 90% or 200 mg/24 hours. MR: above or equal 25% but below or equal 49% reduction of serum M-protein and reduction in 24-hour urine M-protein by 50%-89%.

  From the date of randomization to the date of the first major documented response (CR, PR or MR) that occurs, evaluated up to 35 days after the completion of 6th treatment cycles or if the response occurs earlier.

Secondary Outcomes (3)

• Time to progression (TTP) during treatment with metformin and HDdexa according to criteria for defining response of the International Myeloma Working Group (IMWG)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

• Duration of response (DOR) during treatment with metformin and HDdexa according to criteria for defining response of the International Myeloma Working Group (IMWG)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

• Event free survival (EFS) during treatment with metformin and HDdexa according to criteria for defining response of the International Myeloma Working Group (IMWG)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months

Study Arms (1)

Metformin and HDdexamethasone

EXPERIMENTAL

Metformin XR is initially administered at a dose of 500mg / daily by oral administration for 7 days. Patients who have a good tolerance (lack of adverse events of grade 3 or 4) may be staggered metformin dose to 2500 mg / day. Patients in turn receiving dexamethasone pulse prescription (HDdex). A dose of dexamethasona 40 mg / day taken in a daily for four days every 8 days from 1st to 2nd cycle every 35 days and 1x per week for 4 weeks every 28 days from the 3rd to 6th cycle. The dose will be administered at 4 mg tablets, which are to be swallowed whole by 30 minutes after a meal. Patients over age 75 used 20 mg / day.

Drug: Metformin XR; Drug: Dexamethasone

Interventions

Metformin XR DRUG

500 mg tablet: They take 1-5 tablets of 500 mg after dinner. Starting dose of Metformin XR 500 mg. It will have an increase of 500 mg/day each week up to the maximum tolerance from the 2500 mg / day, during the 6 cycles.

Also known as: Glifage XR

Metformin and HDdexamethasone

Dexamethasone DRUG

4 mg tablet: Patients will use 40 mg per day. They take 5-10 tablets 4mg after breakfast and lunch. Patients over age 75 will use 20 mg / day.

Also known as: Decadron

Metformin and HDdexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18 years;
• Multiple myeloma patients relapsed or refractory to two lines prior to treatment \[at least one line using bortezomib or prior treatment with a suitable alkylating agent (at least six cycles of treatment with alkylating or progressive disease after at least two cycles of treatment with alkylating or treatment with alkylating received as part of a stem cell transplant)\];
• Patients should have failed (progressive disease at or before 60 days of treatment, disease progression ≤6 months after achieving partial response or intolerance to bortezomib) to treatment with bortezomib;
• Patients with oral access to medicines;
• ECOG ≤ 2;
• Blood count: hemoglobin ≥8 g / dL; absolute neutrophil count ≥500 / mm3 and platelet count ≥30.000 / mm3, glomerular filtration rate (GFR) ≥60ml / min and adequate liver function (AST or ALT at levels 3x upper limit of normal, bilirubin in levels no greater than 2x the upper limit of normal, negative pregnancy test before study initiation or accept contraceptive use.

You may not qualify if:

• Patients with known hypersensitivity and / or prior therapy with metformin or its excipients;
• Diabetes mellitus who require insulin use and other oral hypoglycemic agents; patients with a history of hyperglycemia induced by steroids can be entered since HbA1C in screening visit is \<8%;
• leptomeningeal or brain metastases symptomatic or untreated, or spinal cord compression;
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) (with the exception treated or cured chronic HBV and HCV infection, who will be allowed);
• Patients who are using another study medication or who have received drug under study for less than 4 weeks;
• It is allowed concomitant treatment with bisphosphonates; however, treatment should be started before the first dose of study therapy;
• it is not allowed to use of all herbal supplements during the study (including, but not limited to, St. John's wort, kava, None, gingko biloba, dehydroepiandrosterone \[DHEA\], or ginseng). megestrol acetate (Megace) or medroxyprogesterone if used as an appetite stimulant is permitted;
• Uncontrolled situations by intercurrent disease, including, but not limited to, infection ongoing and active, refractory systemic hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric / social disease that would limit compliance with the requirements of study;
• Previous Neoplasms, except skin cancer for over two years;
• Patients who are pregnant or breastfeeding.
• Any major surgery, extensive radiation therapy, chemotherapy delayed toxicity, biological therapy, chemotherapy or immunotherapy within 28 days before study.

Sponsors & Collaborators

• University of Campinas, Brazil: lead

Study Sites (2)

UOPECCAN - Hospital do Câncer de Cascavel

Cascavel, Paraná, Brazil

RECRUITING

Hemocentro - Hospital de Clínicas - State University of Campinas (UNICAMP)

Campinas, São Paulo, Brazil

RECRUITING

Related Publications (4)

• Zi FM, He JS, Li Y, Wu C, Yang L, Yang Y, Wang LJ, He DH, Zhao Y, Wu WJ, Zheng GF, Han XY, Huang H, Yi Q, Cai Z. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 2015 Jan 28;356(2 Pt B):443-53. doi: 10.1016/j.canlet.2014.09.050. Epub 2014 Oct 8.

  PMID: 25305450 BACKGROUND

• Jagannathan S, Abdel-Malek MA, Malek E, Vad N, Latif T, Anderson KC, Driscoll JJ. Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib. Leukemia. 2015 Nov;29(11):2184-91. doi: 10.1038/leu.2015.157. Epub 2015 Jun 25.

  PMID: 26108695 BACKGROUND

• Wu W, Merriman K, Nabaah A, Seval N, Seval D, Lin H, Wang M, Qazilbash MH, Baladandayuthapani V, Berry D, Orlowski RZ, Lee MH, Yeung SC. The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma. Br J Cancer. 2014 Jul 29;111(3):628-36. doi: 10.1038/bjc.2014.307. Epub 2014 Jun 12.

  PMID: 24921909 BACKGROUND

• Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. Metformin in cancer: translational challenges. J Mol Endocrinol. 2012 Mar 29;48(3):R31-43. doi: 10.1530/JME-12-0007. Print 2012 Jun.

  PMID: 22355097 BACKGROUND

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Central Study Contacts

Ademar Dantas da C Júnior, MD

CONTACT

55-45-91351056; ademardcj@gmail.com

Ligia T Macedo, MD

CONTACT

55-19-997942225; ligiamed@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: November 4, 2016
• First Posted: November 18, 2016
• Study Start: January 1, 2017
• Primary Completion: February 1, 2018
• Study Completion: February 1, 2020
• Last Updated: May 2, 2017

Record last verified: 2016-11

Data Sharing

• IPD Sharing: Will not share

Locations

BR (2)