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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by University of Michigan Cancer Center
Sponsor:
Information provided by (Responsible Party):
University of Michigan Cancer Center
ClinicalTrials.gov Identifier:
NCT01750567
First received: October 2, 2012
Last updated: July 5, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Relapsed Chronic Lymphocytic Leukemia
Drug: Metformin
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Pilot Study of Metformin Therapy in Patients With Relapsed Chronic Lymphocytic Leukemia and Untreated CLL Patients With Genomic Deletion 11q

Resource links provided by NLM:


Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:
  • Time to treatment failure [ Time Frame: every 3 months ] [ Designated as safety issue: Yes ]

    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 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 or platelet count <100,000)


Secondary Outcome Measures:
  • Time to first therapy (TTFT) in previously untreated 11q CLL subsets only. [ Time Frame: from time of diagnosis to time of first treatment with anti‐neoplastic chemotherapy. ] [ Designated as safety issue: Yes ]
    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

  • changes in the rate of increase of absolute lymphocyte count while on metformin therapy [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 53
Study Start Date: October 2012
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Glucophage

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 (see Appendix A)
  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 bilirubin < ULN (exception of Gilbert disease) serum creatinine less than or equal to 1.5 in males, or 1.4 in female GFR > 60

  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 17 History of metabolic acidosis Ongoing or active infection concerning for sepsis or SIRS

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01750567

Locations
United States, Michigan
University of Michigan Comprehensive Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Sami Malek, MD    734-936-5310    smalek@med.umich.edu   
Contact: Erlene Seymour, MD    734-647-2892    ekuizon@med.umich.edu   
Principal Investigator: Sami Malek, MD         
Sub-Investigator: Daniel Lebovic, MD         
Sub-Investigator: Erlene Seymour, MD         
Sponsors and Collaborators
University of Michigan Cancer Center
Investigators
Principal Investigator: sami Malek, MD University of Michigan Cancer Center
  More Information

No publications provided

Responsible Party: University of Michigan Cancer Center
ClinicalTrials.gov Identifier: NCT01750567     History of Changes
Other Study ID Numbers: UMCC 2012.025
Study First Received: October 2, 2012
Last Updated: July 5, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Michigan Cancer Center:
Relapsed Chronic Lymphocytic Leukemia
untreated CLL patients
genomic deletion 11q

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Metformin
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 29, 2014