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

A Phase II Pilot Study of Metformin Therapy in Patients With Relapsed Chronic Lymphocytic Leukemia and Untreated CLL Patients With Genomic Deletion 11q

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Relapsed Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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
2. Patients who relapse after receiving a one or more courses of fludarabine, bendamustine, cytoxan, rituxan, chlorambucil, or campath based therapy.

3. 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
4. Patient with confirmed del11q mutation may be included if untreated.
5. Age > or equal to 18 years old and < 80 years of age during the course of therapy
6. ECOG performance 0-2
7. Life expectancy > 12 months

8. Patients must have normal organ function as defined as below:

   • AST and ALT < 2 times the upper limit of normal
   • alkaline phosphatase < 2 ULN
   • serum conjugated bilirubin < 1.5 ULN (exception of Gilbert disease)
   • serum creatinine less than or equal to 1.5 in males, or 1.4 in females
   • GFR > 59
9. Ability to understand and the willingness to sign a written informed consent document
10. Patient must be able to drink and eat more than 75% of their usual daily meals.

Exclusion Criteria:

1. Patients with active CLL disease requiring urgent chemotherapy
2. Patients may not be receiving any other investigational agents.
3. Patients less than 30 days from last treatment for CLL.
4. History of allergic reactions attributed to metformin or other biguanides.
5. Known diabetes (type 1 or 2), fasting glucose > or equal to 7.0 mmol/L (126 mg/dL), or HgbA1C > 6.5
6. Currently taking metformin, sulfonylureas, thiazolidinediones or insulin for any reason
7. Current or planned pregnancy or lactation in women of child bearing age (confirmed by negative pregnancy test prior to start of therapy).
8. 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

9. 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

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 (Glucophage); 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; Metformin is an antidiabetic drug which is an inexpensive and generally well tolerated medication.; Other Names: Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: 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.; An increase of Rai Stage (0-3) by one stage.; 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).; 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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first therapy (TTFT) in previously untreated 11q CLL subsets only.	To evaluate TTFT in untreated patients, the product-limit method of Kaplan and Meier will be used similarly to the primary endpoint. The main difference between this endpoint and the primary endpoint is that TTFT will be defined from the date of CLL diagnosis for untreated delq11 patients	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	Longitudinal lymphocyte counts will be modeled using mixed models methodology, whereby both fixed effects (dose of metformin) and random effects (intercept - starting lymphocyte count) can be modeled.	Until the patient meets failure criteria and stops Metformin
Change in size of clinically appreciated lymphadenopathy in cm and splenomegaly while on metformin therapy	The proportion of patients that begin metformin therapy with these conditions will be summarized, along with the proportions at study defined clinical assessment points during therapy. No statistical models will be employed, but proportions and 95% exact binomial confidence intervals will be reported for descriptive purposes.	Baseline up to 3 months after completing metformin therapy
Change in number of clinically appreciated lymphadenopathy and splenomegaly while on metformin therapy	The proportion of patients that begin metformin therapy with these conditions will be summarized, along with the proportions at study defined clinical assessment points during therapy. No statistical models will be employed, but proportions and 95% exact binomial confidence intervals will be reported for descriptive purposes.	Baseline up to 3 months after completing metformin therapy

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Sami Malek, MD, University of Michigan Rogel Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2012
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): May 1, 2024

Study Registration Dates

• First Submitted: October 2, 2012
• First Submitted That Met QC Criteria: December 12, 2012
• First Posted (Estimated): December 17, 2012

Study Record Updates

• Last Update Posted (Estimated): August 31, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Relapsed Chronic Lymphocytic Leukemia; untreated CLL patients; genomic deletion 11q
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: UMCC 2012.025

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes