A Pilot Study of Metformin Therapy in Patients With Relapsed Chronic Lymphocytic Leukemia (CLL) and Untreated CLL

NCT01750567 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: UMCC 2012.025
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

Brief Summary

Metformin is an antidiabetic drug which is an inexpensive and generally well tolerated medication. More recently metformin has been shown to act against carcinomas by two mechanisms: 1) an indirect, insulin-dependent mechanism which sensitizes tissues to insulin, inhibits hepatic gluconeogenesis, and stimulates uptake of glucose in muscle, thereby reducing fasting blood glucose and circulating levels of insulin, lowering the pro survival activity of the insulin/INSR axis, and 2) a direct, insulin-independent mechanism which activates the AMP-activated protein kinase (AMPK) pathway and leads to inhibition of the mTOR pathway. Given the investigators preliminary published data on insulin and mTOR inhibition\[1\] metformin is an attractive candidate for a pilot clinical trial in CLL patients.

Conditions

Relapsed Chronic Lymphocytic Leukemia

Keywords

Relapsed Chronic Lymphocytic Leukemia; untreated CLL patients; genomic deletion 11q

Outcome Measures

Primary Outcomes (1)

• Time to treatment failure

  While patients are on metformin therapy, time to treatment failure will be defined as one or all of the following criteria: 1. ALC \> 5000 on 3 occasions after start of metformin treatment and increasing by 25% or more on each occasion, which will be measured every 3 months. 2. An increase of Rai Stage (0-3) by one stage. 3. An increase in any lymph node by \>50% as assessed by either physical exam (all patients) or CT scanning (only if ordered as part of routine clinical management). 4. Worsening cytopenias (Hemoglobin \<11 g/dl) associated with a bone marrow biopsy result indicating advanced stage CLL (packed CLL marrow).

  Until the patient meets failure criteria and stops Metformin; up to 6 months after start of metformin therapy and yearly thereafter.

Secondary Outcomes (4)

• Time to first therapy (TTFT) in previously untreated 11q CLL subsets only.

  from time of diagnosis to time of first treatment with anti-neoplastic chemotherapy.

• Changes in the rate of increase of absolute lymphocyte count while on metformin therapy

  Until the patient meets failure criteria and stops Metformin

• Change in size of clinically appreciated lymphadenopathy in cm and splenomegaly while on metformin therapy

  Baseline up to 3 months after completing metformin therapy

• Change in number of clinically appreciated lymphadenopathy and splenomegaly while on metformin therapy

  Baseline up to 3 months after completing metformin therapy

Study Arms (1)

Metformin (Glucophage)

EXPERIMENTAL

The starting dose of metformin will be 500 mg po daily for one week. The dose can be escalated to 500 mg twice a day after one week, and further escalated to the final dose of 1000 mg twice a day in week 3 if the medication is tolerated without adverse side effects (refer to holding parameters described in section 9.3.3). All doses should be administered with food to decrease gastrointestinal upset.

Drug: Metformin

Interventions

Metformin DRUG

Metformin is an antidiabetic drug which is an inexpensive and generally well tolerated medication.

Also known as: Glucophage

Metformin (Glucophage)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients should have a confirmed diagnosis of chronic lymphocytic leukemia defined as all of the following:
• ALC \> 5000
• Positive for either CD19 or CD 20 together with CD23 and CD5.
• Less than 55% atypical cells
• Patients who relapse after receiving a one or more courses of fludarabine, bendamustine, cytoxan, rituxan, chlorambucil, or campath based therapy.
• Patients should have findings of relapse by one or both of the following:
• ALC \> 5000 on 2 consecutive occasions and increasing
• Any increase in lymphadenopathy over best response that has persisted for more than 3 months
• Patient with confirmed del11q mutation may be included if untreated.
• Age \> or equal to 18 years old and \< 80 years of age during the course of therapy
• ECOG performance 0-2
• Life expectancy \> 12 months
• Patients must have normal organ function as defined as below:
• AST and ALT \< 2 times the upper limit of normal
• alkaline phosphatase \< 2 ULN

You may not qualify if:

• Patients with active CLL disease requiring urgent chemotherapy
• Patients may not be receiving any other investigational agents.
• Patients less than 30 days from last treatment for CLL.
• History of allergic reactions attributed to metformin or other biguanides.
• Known diabetes (type 1 or 2), fasting glucose \> or equal to 7.0 mmol/L (126 mg/dL), or HgbA1C \> 6.5
• Currently taking metformin, sulfonylureas, thiazolidinediones or insulin for any reason
• Current or planned pregnancy or lactation in women of child bearing age (confirmed by negative pregnancy test prior to start of therapy).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and sepsis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Conditions which would increase risk of lactic acidosis including:
• Known alcoholism or ingestion of more than 3 alcoholic beverages per day
• History of congestive heart failure defined as NYHA class III or IV
• History of metabolic acidosis
• Ongoing or active infection concerning for sepsis or SIRS

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead

Study Sites (1)

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Metformin

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Sami Malek, MD

  University of Michigan Rogel Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 2, 2012
• First Posted: December 17, 2012
• Study Start: November 1, 2012
• Primary Completion: February 28, 2025
• Study Completion: February 28, 2025
• Last Updated: September 9, 2025

Record last verified: 2025-09

Locations

US (1)