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

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

Overview[ - collapse ][ - ]

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	Relapsed Chronic Lymphocytic Leukemia
Intervention	Drug: Metformin
Phase	Phase 2
Sponsor	University of Michigan Cancer Center
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

Tracking Information[ + expand ][ + ]

First Received Date	October 2, 2012
Last Updated Date	July 5, 2013
Start Date	October 2012
Estimated Primary Completion Date	October 2016
Current 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: 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 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 or platelet count <100,000)
Current 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.

Descriptive Information[ + expand ][ + ]

Brief Title	A Pilot Study of Metformin Therapy in Patients With Relapsed Chronic Lymphocytic Leukemia (CLL) and Untreated CLL
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
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.
Detailed Description	Not Provided
Study Type	Interventional
Study Phase	Phase 2
Study Design	Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Relapsed Chronic Lymphocytic Leukemia
Intervention	Drug: Metformin Metformin is an antidiabetic drug which is an inexpensive and generally well tolerated medication. Other Names: Glucophage
Study Arm (s)	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.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	53
Estimated Completion Date	October 2016
Estimated Primary Completion Date	October 2016
Eligibility 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
Gender	Both
Ages	18 Years
Accepts Healthy Volunteers	No
Contacts	Not Provided
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01750567
Other Study ID Numbers	UMCC 2012.025
Has Data Monitoring Committee	Yes
Information Provided By	University of Michigan Cancer Center
Study Sponsor	University of Michigan Cancer Center
Collaborators	Not Provided
Investigators	Principal Investigator: sami Malek, MD University of Michigan Cancer Center
Verification Date	July 2013

Locations[ + expand ][ + ]

University of Michigan Comprehensive Cancer Center	Ann Arbor, Michigan, United States, 48109 Contact: Sami Malek, MD \| 734-936-5310 \| smalek@med.umich.edu Principal Investigator: Sami Malek, MD Recruiting