Atorvastatin for Melanoma

Overseen By Wesley Yu, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: OHSU Knight Cancer Institute

Must not be taking: Statins, Cyclosporine, Erythromycin, others

Disqualifiers: Investigational agents, Hypersensitivity, Psychiatric disorder, others

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: Unknown

Duration: 5 years

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This clinical trial tests whether atorvastatin prevents metastasis of resected high-risk stage IIA, IIB or IIIA melanoma. The vast majority of melanomas are diagnosed at an early, localized stage. However, approximately 10-15% of these localized melanomas will eventually metastasize, despite appropriate local treatment. Once metastasis occurs, median survival is less than two years. Melanomas at high risk of metastasis can be identified by gene expression profiling. Statin drugs, like atorvastatin, have been used to treat high cholesterol for the prevention of major adverse cardiovascular events, but not for preventing melanoma metastasis. Statins could prevent melanoma metastasis through decreasing tumor cell migration, decreasing tumor cell adhesion, and increasing immune system response. Statins are also efficient inhibitors of new lymphatic vessels formation. Since tumor lymphatic vessels serve as highways to lymph nodes and may suppress immune system responses, statins may block a critical step towards melanoma metastasis. Using atorvastatin may have the potential to prevent metastasis and improve outcomes in patients with resected high-risk melanoma.

Do I have to stop taking my current medications for the trial?

The trial requires that you stop taking any statins if you have been on them in the past year. Additionally, you cannot take cyclosporine, erythromycin, fibrates, niacin, or any other medication that is not compatible with statin treatment. For other medications, the protocol does not specify, so it's best to discuss with the trial team.

Is atorvastatin generally safe for humans?

Atorvastatin, also known as Lipitor, is a medication commonly used to lower cholesterol and has been studied for its safety in humans. In clinical trials with similar drugs like lovastatin, no significant differences in adverse events were found compared to placebo, suggesting a good safety profile. ^{1 2 3 4 5}

How does the drug Atorvastatin differ from other treatments for melanoma?

Atorvastatin, commonly used to lower cholesterol, is being explored for melanoma treatment, which is unique because it is not a standard cancer therapy like immune checkpoint inhibitors or BRAF-MEK inhibitors. This approach is novel as it investigates the potential of a cardiovascular drug in cancer treatment, possibly offering a new mechanism of action compared to existing melanoma therapies. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Atorvastatin for treating melanoma?

Research suggests that statins, like Atorvastatin, may have potential in preventing melanoma due to their lipid-lowering and anti-inflammatory effects. However, specific studies on Atorvastatin for melanoma are limited, and more research is needed to confirm its effectiveness. ^{1 2 3 5 11}

Who Is on the Research Team?

Wesley Yu, M.D.

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a specific type of skin cancer called high-risk stage IIA cutaneous melanoma that's been surgically removed. They must not have had other melanoma treatments or certain medications, and should be generally healthy with no evidence of cancer spread. Women who can get pregnant must agree to use birth control.

Inclusion Criteria

My melanoma test result is class 2B.

My scans show no signs of cancer spread, and any suspicious areas have been tested and are not cancerous.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

I am currently on a statin or was on one in the past year.

I am not taking medication that interferes with statin treatment.

Participant who in the opinion of the investigator, has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive atorvastatin or placebo orally once per day for up to 5 years, with regular CT and/or MRI scans to monitor disease progression

5 years

Follow-up

Participants are monitored for recurrence-free survival, distant metastasis-free survival, and overall survival after treatment completion

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Atorvastatin

Trial Overview The study tests if atorvastatin, commonly used for cholesterol, can prevent the spread (metastasis) of resected high-risk melanoma by affecting tumor cell behavior and immune response. Participants will either receive atorvastatin or a placebo while being monitored through scans and health records.

How Is the Trial Designed?

Group I: Arm II (Atorvastatin) Experimental Treatment 4 Interventions

Patients receive atorvastatin PO daily (QD) in the absence of disease progression or unacceptable toxicity for up to 5 years and undergo CT and/or undergo MRI throughout the study.

Group II: Arm I (Placebo) Placebo Group 4 Interventions

Patients receive placebo PO daily (QD) in the absence of disease progression or unacceptable toxicity for up to 5 years and undergo CT and/or MRI throughout the study.

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

Approved in European Union as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in United States as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Canada as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia
• Prevention of cardiovascular disease

Approved in Japan as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in China as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Approved in Switzerland as Lipitor for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Homozygous familial hypercholesterolemia

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Kuni Foundation

Collaborator

Trials

3

Recruited

270+

Published Research Related to This Trial

A systematic review of 16 randomized controlled trials involving 62,197 participants found that lipid-lowering medications (statins and fibrates) showed a 10% reduction in melanoma incidence for statins and a 42% reduction for fibrates, although these results were not statistically significant.

The study suggests that while there is some evidence that statins and fibrates may reduce melanoma risk, more research is needed to confirm these findings, and current best practice for melanoma prevention remains limiting UV exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statins and fibrates for preventing melanoma. Dellavalle, RP., Drake, A., Graber, M., et al.[2022]

In a study involving female B6D2F1 mice with melanoma, the combination of lovastatin and TNF-alpha significantly inhibited tumor growth and improved survival rates compared to control and single treatment groups.

The results suggest that lovastatin may enhance the antitumor effects of TNF-alpha, indicating a potential synergistic relationship that could be beneficial for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic antitumor activity of tumor necrosis factor-alpha and lovastatin against MmB16 melanoma in mice. Feleszko, W., Lasek, W., Gołab, J., et al.[2013]

In a randomized, double-blind trial with 80 participants, lovastatin did not show any benefit in reducing melanoma-related biomarkers compared to placebo over a 6-month period.

While lovastatin effectively lowered total serum cholesterol and LDL levels, it did not impact the histopathologic atypia of atypical nevi or any other clinical or molecular markers related to melanoma risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology. Linden, KG., Leachman, SA., Zager, JS., et al.[2021]

Simvastatin triggers apoptosis in human metastatic melanoma cells through the activation of the 15-deoxy-12,14-PGJ2 (15d-PGJ2) signaling pathway, which is dependent on p38 and COX-2, demonstrating its potential as a therapeutic agent against metastatic melanoma.

The apoptotic effect of simvastatin was specific to melanoma cells and did not affect primary human melanocytes, indicating a targeted mechanism that could minimize side effects in normal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autocrine secretion of 15d-PGJ2 mediates simvastatin-induced apoptotic burst in human metastatic melanoma cells. Wasinger, C., Künzl, M., Minichsdorfer, C., et al.[2022]

First-generation isoprenylation inhibitors, specifically the statins like lovastatin and fibrates like gemfibrozil, have shown potential in reducing the incidence of melanoma based on findings from large clinical trials.

The article emphasizes the need to further investigate the chemotherapeutic and chemopreventive effects of these commonly prescribed lipid-lowering medications in the context of melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma chemoprevention: a role for statins or fibrates? Dellavalle, RP., Nicholas, MK., Schilling, LM.[2019]

In a study involving 1,318 melanoma cases and 6,786 matched controls, statin use was not linked to an increased risk of developing cutaneous melanoma, indicating that statins may be safe in this context.

However, statin users showed a significant reduction in Breslow thickness of melanoma tumors, suggesting that statins may help slow the progression of melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed metastasis of melanoma of the skin? Koomen, ER., Joosse, A., Herings, RM., et al.[2007]

Recent advancements in systemic therapies for melanoma, like immune checkpoint inhibitors and BRAF-MEK inhibitors, have significantly improved survival rates, especially for high-risk and advanced cases.

However, these treatments are linked to increased cardiovascular risks, including serious conditions like heart failure and myocardial infarction, highlighting the need for careful cardiovascular risk management in melanoma survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular disease and malignant melanoma. Wang, CY., Zoungas, S., Voskoboynik, M., et al.[2023]

Ipilimumab, while used for melanoma treatment, has a high rate of severe adverse events (over 50% of patients), making it less favorable compared to newer options.

BRAF inhibitors, particularly when combined with mitogen-activated protein kinase inhibitors, show greater efficacy and a better safety profile than ipilimumab, but are only effective in about 50% of melanoma cases with a specific BRAF gene mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous melanoma: Latest developments. Dixon, AJ., Steinman, HK., Nirenberg, A., et al.[2020]

Targeted therapies, such as BRAF inhibitors (vemurafenib and dabrafenib), have shown high efficacy in treating BRAF-mutated metastatic melanoma, significantly improving outcomes for patients with this genetic mutation.

Immunotherapy using monoclonal antibodies targeting CTLA4, PD-1, and PD-L1 has led to exceptionally prolonged responses in some patients, highlighting the importance of personalized treatment approaches in melanoma management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Melanoma: from molecular studies to the treatment breakthrough]. Imianitov, EN.[2018]

Melanoma is a highly aggressive skin cancer, and prior to recent treatments, dacarbazine was the most effective option for improving overall survival, but newer therapies like ipilimumab and BRAF inhibitors have shown limited long-term benefits for most patients.

Current research is focusing on combination therapies that include DNA repair inhibitors, immunomodulators, and targeted therapies to enhance the effectiveness of existing melanoma treatments and overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenging resistance mechanisms to therapies for metastatic melanoma. Tentori, L., Lacal, PM., Graziani, G.[2022]

Immune checkpoint inhibitors, particularly anti-PD-1 antibodies like pembrolizumab and nivolumab, have transformed the treatment of metastatic melanoma, achieving long-term survival rates over 50% in some patients, especially when combined with ipilimumab.

These treatments are generally well tolerated, although the combination of nivolumab and ipilimumab can lead to higher toxicity, prompting ongoing research into new immunotherapy combinations and strategies for patients with poor prognoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 and Novel Combinations in the Treatment of Melanoma-An Update. Gellrich, FF., Schmitz, M., Beissert, S., et al.[2020]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Statins and fibrates for preventing melanoma. [2022]

2. Slovakia pubmed.ncbi.nlm.nih.gov

Synergistic antitumor activity of tumor necrosis factor-alpha and lovastatin against MmB16 melanoma in mice. [2013]

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

A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Autocrine secretion of 15d-PGJ2 mediates simvastatin-induced apoptotic burst in human metastatic melanoma cells. [2022]

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

Melanoma chemoprevention: a role for statins or fibrates? [2019]

6. England pubmed.ncbi.nlm.nih.gov

Is statin use associated with a reduced incidence, a reduced Breslow thickness or delayed metastasis of melanoma of the skin? [2007]

7. England pubmed.ncbi.nlm.nih.gov

Cardiovascular disease and malignant melanoma. [2023]

8. Australia pubmed.ncbi.nlm.nih.gov

Cutaneous melanoma: Latest developments. [2020]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Melanoma: from molecular studies to the treatment breakthrough]. [2018]

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

Challenging resistance mechanisms to therapies for metastatic melanoma. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-PD-1 and Novel Combinations in the Treatment of Melanoma-An Update. [2020]