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

Sponsor

University of Michigan Rogel Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT01750567

Collaborator

(none)

Enrollment

Location

Arm

123.9

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Chronic Lymphocytic Leukemia	Drug: Metformin	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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

Actual Study Start Date :

Nov 1, 2012

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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.]
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 [Until the patient meets failure criteria and stops Metformin]
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.
Change in size of clinically appreciated lymphadenopathy in cm and splenomegaly while on metformin therapy [Baseline up to 3 months after completing 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.
Change in number of clinically appreciated lymphadenopathy and splenomegaly while on metformin therapy [Baseline up to 3 months after completing 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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
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

Ability to understand and the willingness to sign a written informed consent document
Patient must be able to drink and eat more than 75% of their usual daily meals.

Exclusion Criteria:

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: