Relapsed Chronic Lymphocytic Leukemia
Conditions
Keywords
Relapsed Chronic Lymphocytic Leukemia, untreated CLL patients, 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.
Interventions
DRUGMetformin
Metformin is an antidiabetic drug which is an inexpensive and generally well tolerated medication.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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, assessed up to 12 years | 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
| Measure | Time frame | Description |
|---|---|---|
| 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, assessed up to 12 years | 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, assessed up to 12 years | 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, assessed up to 12 years | 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, assessed up to 12 years | The number 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSami Malek, MD
University of Michigan Rogel Cancer Center
Participant flow
Recruitment details
There were 4 screen fails
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Region of Enrollment United States | 37 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 37 |
| other Total, other adverse events | 32 / 37 |
| serious Total, serious adverse events | 3 / 37 |
Outcome results
None listed