Metformin for Chronic Lymphocytic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: Metformin, Sulfonylureas, Insulin

Disqualifiers: Diabetes, Urgent chemotherapy, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 6 months

37 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking metformin, sulfonylureas, thiazolidinediones, or insulin. Also, you cannot join if you are less than 30 days from your last CLL treatment.

What data supports the effectiveness of the drug metformin for chronic lymphocytic leukemia?

Research shows that metformin can induce cell death and prevent the growth of chronic lymphocytic leukemia cells by interfering with their energy use and survival signals. It also enhances the effects of other cancer-fighting drugs, suggesting it could be a helpful addition to leukemia treatment. ^{1 2 3 4 5}

Is Metformin safe for humans?

Metformin, also known by brand names like Glucophage, Fortamet, Glumetza, and Riomet, is a medication commonly used to treat type 2 diabetes and has a well-established safety profile for this condition. It is generally considered safe for human use, with common side effects including stomach upset and diarrhea, but it is important to consult with a healthcare provider for individual advice. ^{3 6 7 8 9}

How does the drug Metformin differ from other treatments for chronic lymphocytic leukemia?

Metformin is unique because it is primarily an oral diabetes medication that has shown potential antitumor activity by inducing cell death and preventing the growth of leukemia cells. Unlike traditional treatments, it works by interfering with the cell cycle of leukemia cells, making it a novel approach for chronic lymphocytic leukemia. ^{1 3 4 10 11}

Research Team

Sami Malek, MD

Principal Investigator

University of Michigan Rogel Cancer Center

Eligibility Criteria

This trial is for adults aged 18-79 with relapsed or untreated chronic lymphocytic leukemia (CLL) who have specific blood cell counts and markers. They must not have diabetes, be taking certain diabetes medications, or require urgent chemotherapy. Participants need to be in stable health without severe heart failure or a history of allergic reactions to metformin.

Inclusion Criteria

My lymph nodes have been swollen for more than 3 months.

My condition worsened after treatment with specific cancer drugs.

I am between 18 and 79 years old.

Exclusion Criteria

Conditions which would increase risk of lactic acidosis including:

I am currently taking medication for diabetes.

I have diabetes with high blood sugar or HgbA1C levels.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive metformin therapy starting at 500 mg daily, escalating to 1000 mg twice a day if tolerated

6 months

Weekly visits for dose escalation in the first 3 weeks, then monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Visits every 3 months

Long-term follow-up

Participants are monitored yearly for treatment failure and other outcomes

Yearly

Treatment Details

Interventions

• Metformin

Trial Overview The study tests Metformin, commonly used for diabetes, on CLL patients. It explores how Metformin affects cancer cells by improving insulin sensitivity and activating pathways that may inhibit cancer growth. This pilot trial aims to see if it's safe and effective in treating CLL.

Participant Groups

Group I: Metformin (Glucophage) Experimental Treatment 1 Intervention

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.

Metformin is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Glucophage for:

• Type 2 diabetes

Approved in United States as Glucophage for:

• Type 2 diabetes

Approved in Canada as Glucophage for:

• Type 2 diabetes

Approved in Japan as Glucophage for:

• Type 2 diabetes

Approved in China as Glucophage for:

• Type 2 diabetes

Approved in Switzerland as Glucophage for:

• Type 2 diabetes

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Findings from Research

Recent advancements in treatment options for chronic lymphocytic leukemia (CLL) include novel targeted therapies like obinutuzumab and ofatumomab, which are effective and well-tolerated, especially for elderly patients or those with other health issues.

Ibrutinib and idelalisib show excellent efficacy in CLL, particularly for patients with 17p deletions, while the newly FDA-approved venetoclax offers promising results for those with relapsed or refractory disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expanding the armamentarium for chronic lymphocytic leukemia: A review of novel agents in the management of chronic lymphocytic leukemia. Marini, BL., Samanas, L., Perissinotti, AJ.[2021]

In a phase II pilot study involving 24 patients with chronic lymphocytic leukemia (CLL) who had previously undergone chemotherapy, alemtuzumab demonstrated significant efficacy, with 33% of patients achieving a major response and a median survival time of 35.8 months.

Despite its effectiveness, the treatment was associated with a high incidence of opportunistic infections due to low lymphocyte counts, suggesting that future studies should implement mandatory antimicrobial prophylaxis to enhance patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. Rai, KR., Freter, CE., Mercier, RJ., et al.[2017]

Subcutaneous alemtuzumab is effective in treating residual disease in chronic lymphocytic leukemia (CLL), with 23 out of 29 evaluable patients responding positively to the treatment after self-administration.

Higher plasma levels of alemtuzumab at the end of treatment were associated with longer response durations, highlighting the importance of monitoring drug levels and minimal residual disease in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Self-administered, subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia. Wierda, WG., Kipps, TJ., Keating, MJ., et al.[2021]

In a study of 141 patients with chronic lymphocytic leukemia (CLL) treated with venetoclax, the overall response rate was 72%, indicating that venetoclax is an effective treatment option, especially for patients with mutations that typically resist other therapies like ibrutinib.

The treatment was generally well-tolerated, with 85% of patients reaching the maximum recommended dose of 400 mg daily, although some experienced adverse effects such as neutropenia (47.4%) and tumor lysis syndrome (13.4%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Mato, AR., Thompson, M., Allan, JN., et al.[2020]

Chronic lymphocytic leukaemia (CLL) primarily affects older adults, particularly men, and asymptomatic patients can expect a life expectancy similar to the general population, often requiring only monitoring.

Chlorambucil is the standard treatment for symptomatic CLL, while fludarabine is used if chlorambucil is ineffective; however, combination therapies do not show improved outcomes compared to these single-agent treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukaemia: only treat when symptomatic. [2013]

References

1. Czech Republic pubmed.ncbi.nlm.nih.gov

[Therapeutic Options for "Slow go" Patients with Chronic Lymphocytic Leukemia]. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Investigating and targeting chronic lymphocytic leukemia metabolism with the human immunodeficiency virus protease inhibitor ritonavir and metformin. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Expanding the armamentarium for chronic lymphocytic leukemia: A review of novel agents in the management of chronic lymphocytic leukemia. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells. [2018]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Influence of Hyperglycemia on the Prognosis of Patients with Diffuse Large B-Cell Lymphoma. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. [2017]

7. United States pubmed.ncbi.nlm.nih.gov

Self-administered, subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia. [2021]

8. Italy pubmed.ncbi.nlm.nih.gov

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. [2021]

10. England pubmed.ncbi.nlm.nih.gov

A clinical update on chronic lymphocytic leukemia. II. Critical analysis of current chemotherapeutic modalities. [2019]

11. France pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukaemia: only treat when symptomatic. [2013]