Repurposing Metformin As a Leukemia-preventive Drug in CCUS and LR-MDS

NCT04741945 | Recruiting Phase 2 DMC

• 1 other identifier: STOP-LEUKEMIA
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single-arm pilot study of the feasibility and safety of metformin in patients with clonal cytopenia of undetermined significance (CCUS) or lower-risk myelodysplastic neoplasms (LR-MDS).

Conditions

Preleukemia; Myelodysplastic Neoplasm; Cytopenia; Preleukemic Anemia

Keywords

Metformin; Myelodysplastic Neoplasm; Clonal Cytopenia of Undetermined Significance; Safety; Feasibility; Bone Marrow Adipose Tissue; Gut Microbiota; Intestinal Permeability

Outcome Measures

Primary Outcomes (5)

• Safety as assessed by the number of serious adverse events including any suspected unexpected serious adverse reactions

  To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients.

  From inclusion to 12 months of study treatment

• Safety as assessed by median maximum tolerated dose in mg/day

  To assess safety of metformin treatment in this off-label indication by median maximum tolerated dose and a description of any changes in individual medication doses.

  From inclusion to 12 months of study treatment

• Feasibility as assessed by rates of recruitment/refusal rates

  To assess feasibility of the study protocol in terms of recruitment and refusal rates.

  From inclusion to 12 months of study treatment

• Feasibility as assessed by 12 months follow-up, i.e., study completion, rate

  To assess feasibility of the study protocol in terms of rate of study completion. To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients; drop-out rates; and a description of any changes in individual medication doses including median maximum tolerated dose.

  From inclusion to 12 months of study treatment

• Feasibility as assessed by rate of compliance to protocol procedures

  To assess feasibility of the study protocol in terms of rate of adherence to protocol procedures (study medication and study procedures).

  From inclusion to 12 months of study treatment

Secondary Outcomes (25)

• Interim efficacy: Mutational burden as assessed by change in variant allele frequency

  From inclusion to 12 months of study treatment

• Interim efficacy: Patient-reported outcome measures based on the EORTC QLQ-C30

  From inclusion to 4 months of study treatment

• Interim efficacy: Patient-reported outcome measures based on the EORTC QLQ-C30

  From inclusion to 12 months of study treatment

• Interim efficacy: Patient-reported outcome measures based on the SF-36

  From inclusion to 4 months of study treatment

• Interim efficacy: Patient-reported outcome measures based on the SF-36

  From inclusion to 12 months of study treatment

Study Arms (1)

Metformin

EXPERIMENTAL

2000 mg/day metformin for 12 months.

Drug: Metformin

Interventions

Metformin DRUG

2000 mg/day metformin for 12 months (1000 mg b.i.d.) with a slow up-titration six weeks prior to full dose treatment.

Metformin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A diagnosis of:
• LR-MDS according to the revised international prognostic scoring system (IPSS-R), i.e., very low- or low-risk disease (IPSS-R score ≤3) in addition to a bone marrow blast percentage \<5 OR
• CCUS defined as the presence of somatic mutation(s) or cytogenetic abnormality not diagnostic of MDS or any other malignancy in the context of persistent cytopenia (\>6 months) with other common causes of cytopenia ruled out in the setting of bone marrow morphology that is not diagnostic of MDS or any other malignancy, and hematolytic conditions have been ruled out. Peripheral blood cytopenia is defined as hemoglobin (hgb) \<11.3 g/dL (7 mmol/L) in women and hgb \<12.9 g/dL (8 mmol/L) in men, platelet count \<150 x 109/L, or neutrophil count \<1.8 x 109/L
• Menopause, if being a female, defined as females \>45 years of age who have experienced amenorrhea for minimum 12 months, without any other obvious pathological or physiological cause
• ≥18 years of age
• Written informed consent
• Willingness to comply with mandatory aspects of the protocol
• Ability to swallow pills

You may not qualify if:

• Any prior treatment with metformin
• A diagnosis of diabetes mellitus
• Therapeutic radiation, immunosuppressive therapy (with the exception of corticosteroids), or chemotherapy within the past year
• Treatment with granulocyte colony-stimulating factor within the past 30 days
• Prior therapy with hypomethylating agents (i.e., azacitidine, decitabine)
• eGFR \<45 mL/min
• Performance status according to the Eastern Cooperative Oncology Group \>2
• Other active malignancy within the past five years
• Uncontrolled comorbidity including impaired hepatic function (total serum bilirubin \>1.5 × upper limit of the normal range (ULN), serum alanine transaminase \>3 × ULN), chronic hepatitis with decompensated cirrhosis, disabling psychiatric disease, severe neurologic disease, uncontrolled metabolic disease, or severe cardiac disease (NYHA class 3-4)
• Healthy volunteers are eligible to be included in WP0 if they meet all of the following criteria:
• Healthy individuals matched on age, sex, and BMI, if possible, to individual patient participants in WP1
• Written informed consent
• Willingness to comply with mandatory aspects of the protocol
• Use of metformin within the past 3 years
• A diagnosis of diabetes mellitus, rheumatological disorders, autoimmune diseases or other inflammatory disorders, celiac disease, inflammatory bowel disease, or other gastrointestinal disorders or symptoms

Sponsors & Collaborators

• Kirsten Grønbæk: lead
• Steno Diabetes Center Copenhagen: collaborator
• Zealand University Hospital: collaborator
• Van Andel Research Institute: collaborator
• Herlev Hospital: collaborator
• Technical University of Denmark: collaborator
• Region Hovedstadens Apotek: collaborator
• University of Copenhagen: collaborator

Study Sites (1)

Rigshospitalet

Copenhagen, Copenhagen N, 2200, Denmark

RECRUITING

MeSH Terms

Conditions

Preleukemia; Anemia, Refractory, with Excess of Blasts; Cytopenia

Interventions

Metformin

Condition Hierarchy (Ancestors)

Precancerous Conditions; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Kirsten Grønbæk, Professor, MD

  Rigshospitalet, Denmark

  STUDY CHAIR

Central Study Contacts

Kirsten Grønbæk, Professor, MD

CONTACT

+45 35456060; Kirsten.Groenbaek@regionh.dk

Stine Ulrik Mikkelsen, MD

CONTACT

+45 35456071; stine.ulrik.mikkelsen@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD, DMSc

Study Record Dates

• First Submitted: January 19, 2021
• First Posted: February 5, 2021
• Study Start: December 13, 2021
• Primary Completion: February 1, 2026
• Study Completion: February 1, 2026
• Last Updated: November 22, 2024

Record last verified: 2024-11

Locations

DK (1)