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

• ClinicalTrials.gov Identifier: NCT01750567
• Recruitment Status: Recruiting
• First Posted: December 17, 2012
• Last Update Posted: May 12, 2022
• Sponsor: University of Michigan Rogel Cancer Center
• Information provided by (Responsible Party): University of Michigan Rogel Cancer Center

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 (Clinical Trial)
• Estimated 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: November 2012
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: March 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 Name: Glucophage

Outcome Measures

Primary Outcome Measures :

1. Time to treatment failure [ Time Frame: 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:

   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).

Secondary Outcome Measures :

1. 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. ]
   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
2. Changes in the rate of increase of absolute lymphocyte count while on metformin therapy [ Time Frame: 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.
3. Change in size of clinically appreciated lymphadenopathy in cm and splenomegaly while on metformin therapy [ Time Frame: 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.
4. Change in number of clinically appreciated lymphadenopathy and splenomegaly while on metformin therapy [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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
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

Contacts and Locations

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 Rogel Cancer Center

Investigators

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

More Information

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT01750567
• Other Study ID Numbers: UMCC 2012.025
• First Posted: December 17, 2012
• Last Update Posted: May 12, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by University of Michigan Rogel Cancer Center:

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

Additional relevant MeSH terms:

Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs