5-Fluorouracil + Imiquimod for Skin Cancer

Overseen By Jeff Plowey, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Melissa Pugliano-Mauro

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Metastatic disease, Organ transplant, Autoimmune, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for squamous cell carcinoma (a common type of skin cancer) on the legs, focusing on safety and effectiveness. The treatment involves injecting the chemotherapy drug 5-fluorouracil (5FU) directly into the tumor and sometimes applying a cream called calcipotriene to the skin. The trial includes three groups: one receives both treatments, another receives only the injection, and the last receives standard care without these treatments. Individuals with a biopsy-confirmed squamous cell carcinoma between 1 and 2 cm on their lower legs may be suitable for this trial. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on any other investigational drug treatment or require systemic or localized cancer therapy while participating in the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using 5-fluorouracil (5FU) cream is generally safe for treating certain skin cancers. It lowers the chances of developing squamous cell carcinomas, a common type of skin cancer. Side effects typically occur only at the application site and may include skin irritation, redness, or peeling.

When combined with calcipotriene cream, studies suggest this combination is well-tolerated, causing fewer skin reactions and minor side effects compared to other treatments. One study found that using both creams for just four days significantly cleared skin lesions. This combination also reduced the development of new skin cancers over time.

Since this trial is in its early stages, the main goal is to carefully monitor safety and how well participants handle the treatment. Early-phase trials focus on ensuring the treatment's safety. It is reassuring that 5FU is already approved for other skin conditions, supporting its safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a potentially more effective approach to skin cancer management. Unlike standard treatments like surgical removal, cryotherapy, or topical chemotherapy alone, these investigational treatments combine 5-fluorouracil (5FU) with calcipotriene cream or use 5FU alone. The combination of 5FU and calcipotriene cream targets cancerous lesions with a dual mechanism: 5FU disrupts cancer cell DNA, while calcipotriene enhances the immune response against the tumor. This dual action could lead to a more comprehensive attack on cancer cells. Additionally, the intralesional injection method directly delivers the treatment to the tumor site, which might increase effectiveness and reduce systemic side effects.

What evidence suggests that this trial's treatments could be effective for skin cancer?

Studies have shown that 5-fluorouracil (5-FU) effectively treats skin cancers, including squamous cell carcinoma (SCC), with some studies indicating success in over 90% of cases for certain skin cancers. In this trial, one group of participants will receive 5-FU alone, while another group will receive a combination of 5-FU and calcipotriene, a form of vitamin D used in skin treatments. Research suggests that combining 5-FU with calcipotriene not only treats early skin cancer but also helps prevent further SCC development by boosting the body's immune response against abnormal cells. Overall, using these treatments together could be a promising way to address SCC on the skin. ^{1 6 7 8 9}

Who Is on the Research Team?

Melissa Pugliano-Mauro, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for adults with biopsy-confirmed squamous cell carcinoma (SCC) on the lower legs, who are expected to live more than a year and have good performance status. They must not be on other investigational treatments or have had cancer therapy within four weeks. Women of childbearing potential must test negative for pregnancy and use contraception.

Inclusion Criteria

I have a skin cancer spot between 1.0 and 2.0 cm on my leg below the knee.

Subjects must be willing to adhere to the instructions of the Investigator and his research team and sign an Informed Consent Form prior to entry into the study

Female patient of childbearing potential has a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible

Exclusion Criteria

I haven't had cancer treatment in the last 4 weeks or have recovered from its side effects.

I have fully recovered from any major surgery before starting treatment.

I use topical steroids or creams for a skin condition as advised by my doctor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly intralesional injections of 5-fluorouracil (5FU) for 3 weeks, with a subset also receiving topical imiquimod

3 weeks

3 visits (in-person)

Surgical Resection

Lesions are surgically resected to render patients disease-free

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• 5-fluorouracil
• Imiquimod 5% cream

Trial Overview The study tests injecting a chemotherapy drug called 5-fluorouracil (5FU) directly into SCC tumors in the lower extremities, with or without an additional topical cream called imiquimod. The aim is to assess safety, tolerability, and how well the tumor responds three weeks post-treatment.

How Is the Trial Designed?

Group I: 5FU Group Experimental Treatment 1 Intervention

5-fluorouracil (5FU) Group participants will receive a 1ml intralesional injection of 5FU 50mg/ml aqueous injectable solution. One injection will be administered once monthly for 3 month. Injections will occur on d0, d28, and d56. Standard of care will be administered on d84 of study and lesion will be surgical resected.

Group II: 5FU + 0.005% Calcipotriene cream Group Experimental Treatment 2 Interventions

5-fluorouracil (5FU) + 0.005% calcipotriene cream Group participants will receive intralesional 5FU as in the previous group, additionally participants will also receive two (2) times daily for four (4) days one (1) day after each of three (3) 5FU injections topical application of 0.005% calcipotriene cream to the same lesion. Standard of care will be administered on d84 of study and lesion will be surgical resected.

Group III: Control Group Active Control 1 Intervention

Control group will receive neither 5-fluorouracil (5FU) injection nor topical 0.005% calcipotriene cream. This group will receive standard of care only. Lesion will be surgical resected on day 84 of study.

5-fluorouracil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in European Union as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Canada as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Japan as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Who Is Running the Clinical Trial?

Melissa Pugliano-Mauro

Lead Sponsor

Trials

3

Recruited

90+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Topical 5-fluorouracil (5-FU) is an effective treatment for various dermatologic conditions, with the strongest evidence supporting its use for actinic keratosis, squamous cell carcinoma, and basal cell carcinoma, based on a review of 34 articles including 16 randomized controlled trials.

The systematic review highlights the wide range of efficacy of topical 5-FU across different skin diseases, indicating its versatility as a therapeutic option in dermatology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical 5-fluorouracil in dermatologic disease. Prince, GT., Cameron, MC., Fathi, R., et al.[2018]

In a study of 30 elderly patients with complex eyelid basal cell carcinomas (BCCs) who were unfit for surgery, both imiquimod 5% and fluorouracil 1% creams showed promising long-term efficacy, with complete tumor resolution in 10 patients using imiquimod and 8 patients using fluorouracil after 12 to 16.5 weeks.

While imiquimod was associated with more side effects like skin erythema and chemical conjunctivitis, fluorouracil had a more tolerable side-effect profile, suggesting that both treatments can be effective alternatives to surgery for patients with significant co-morbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of imiquimod 5% and fluorouracil 1% creams in medical monotherapy of complex eyelid basal cell carcinomas. Singh, M., Mehta Grewal, A., Singh, H., et al.[2022]

In a study involving seven patients with advanced squamous cell carcinoma of the skin, six patients showed positive responses to treatment with cisplatin and 5-fluorouracil, including three complete responses and three partial responses.

One patient remained alive and disease-free two years after treatment, suggesting that the combination of cisplatin and 5-FU is a promising and effective regimen for this type of cancer, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin. Khansur, T., Kennedy, A.[2022]

In a study involving 5700 subjects, 5-fluorouracil was found to significantly reduce the overall risk of developing keratinocyte carcinoma compared to imiquimod, with an adjusted hazard ratio of 0.86.

Despite the overall effectiveness of 5-fluorouracil, there were no significant differences in the risk of specific types of keratinocyte carcinoma (squamous or basal cell) or in the cumulative risk over 2 and 5 years between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: A cohort study. Neugebauer, R., Su, KA., Zhu, Z., et al.[2020]

In a study of 5700 adults with actinic keratoses, 5-fluorouracil was found to significantly reduce the short-term risk of developing subsequent AKs compared to imiquimod, with a 4.54% lower cumulative risk over 2 years.

However, there was no significant long-term difference in the risk of subsequent AKs between the two treatments after 5 years, indicating that while 5-fluorouracil is effective in the short term, its long-term benefits may not be as pronounced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A real-world, community-based cohort study comparing the effectiveness of topical fluorouracil versus topical imiquimod for the treatment of actinic keratosis. Neugebauer, R., Levandoski, KA., Zhu, Z., et al.[2019]

A 63-year-old man developed a seborrheic dermatitis-like reaction on his face after using topical 5-fluorouracil on his arms for 7 days, indicating that distant skin reactions can occur with this medication.

The facial dermatitis resolved after stopping the treatment and recurred upon reapplication, confirming a direct link between the drug and the adverse effect, although the exact mechanism behind this distant reaction remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical Application of 5-Fluorouracil Associated with Distant Seborrheic Dermatitis-like Eruption: Case Report and Review of Seborrheic Dermatitis Cutaneous Reactions after Systemic or Topical Treatment with 5-Fluorouracil. Werbel, T., Cohen, PR.[2020]

In a small study of 5 patients with non-resectable melanoma metastases, a topical combination of imiquimod and 5-fluorouracil resulted in a clinical response in 44 out of 45 treated lesions, indicating strong efficacy.

The treatment not only led to significant tumor responses but also prevented the development of new lesions, suggesting it may help achieve locoregional control through an induced antitumor immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical treatment of cutaneous metastases of malignant melanoma using combined imiquimod and 5-fluorouracil. Florin, V., Desmedt, E., Vercambre-Darras, S., et al.[2022]

In a report involving three patients undergoing continuous infusion of 5-fluorouracil (5-FU) for solid tumors, significant inflammation of solar keratoses was observed, a side effect previously noted in only three other cases.

Interestingly, this inflammatory reaction led to the clearance of most solar keratoses, suggesting a potential beneficial effect of 5-FU on these skin lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammation of solar keratoses following systemic 5-fluorouracil. Bataille, V., Cunningham, D., Mansi, J., et al.[2013]

In a study of 64 patients with actinic keratosis (AK), those who used a combined regimen of 5-fluorouracil (5-FU) and imiquimod creams showed significant clearing of their AKs by the end of three months, with 48 patients completing the treatment.

The combined therapy resulted in localized inflammatory responses at the treatment sites, which were manageable and did not affect surrounding skin, indicating that this method is both effective and convenient compared to using each cream separately.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The treatment of actinic keratoses with a combination of 5-fluorouracil and imiquimod creams. Price, NM.[2018]

Topical 5-fluorouracil (5-FU) is effective for treating actinic keratosis and early skin cancers, as demonstrated in a patient with diffuse actinic damage who showed no inflammatory response in previously treated basal cell carcinoma (BCC) areas.

Imiquimod, used 10 years prior for the BCC, not only targets atypical keratinocytes but may also provide photoprotective effects, suggesting a long-term benefit in preventing inflammation and further skin damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imiquimod induces sustained remission of actinic damage: a case report spanning one decade of observation. Knackstedt, TJ., Quitadamo, M.[2018]

A new scale was developed to reliably measure the toxicity of topical 5% 5-fluorouracil, focusing on parameters like erythema and crusting, which are common side effects.

The scale demonstrated high reliability with an intraclass correlation of 0.82 among 13 raters, indicating it can be effectively used by both dermatologists and non-dermatologists to assess treatment toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measuring the severity of topical 5-fluorouracil toxicity. Korgavkar, K., Firoz, EF., Xiong, M., et al.[2017]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10680462/

Evaluating the Efficacy and Safety of 4% 5-Fluorouracil ... Treatment with 4% 5-fluorouracil cream was highly efficacious, safe, and prevented disease recurrence in approximately 27% of patients who achieved complete ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25950503/

Long-term Efficacy of Topical Fluorouracil Cream, 5 ... - PubMed Our results indicate that a single course of fluorouracil cream, 5%, effectively reduces AK counts and the need for spot treatments for longer than 2 years.

3. sciencedirect.com sciencedirect.com/science/article/pii/S0022202X17330452

Five-Year Results of a Randomized Controlled Trial ... Our finding that imiquimod has a tumor-free survival of 80.5% after 5 years of follow-up is comparable with findings of other studies. A recent randomized ...

4. jaad.org jaad.org/article/S0190-9622(21)02390-2/fulltext

Topical 5% 5-fluorouracil versus procedural modalities for ... This study provides real-world treatment outcomes of topical 5-FU for both SCCIS and sBCC, showing an overall success rate of greater than 90% ( ...

5. jamanetwork.com jamanetwork.com/journals/jamadermatology/fullarticle/480680

Effect of a 1-Week Treatment With 0.5% Topical ... Results At 4 weeks, mean actinic keratosis lesion count was reduced by 62.4% in the 0.5% fluorouracil group vs 28.8% in the vehicle group (P<.001), and complete ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/fluorouracil-topical-route/description/drg-20063877

Fluorouracil (topical route) - Side effects & dosage Fluorouracil topical is used to treat actinic or solar keratoses and a type of skin cancer called superficial basal cell carcinoma.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/016831Orig1s063lbl.pdf

EFUDEX® (fluorouracil) TOPICAL SOLUTIONS AND CREAM ... Safety and efficacy in other indications have not been established. The diagnosis should be established prior to treatment, since this method ...

8. dermnetnz.org dermnetnz.org/topics/5-fluorouracil-cream

Fluorouracil (5-FU): Drug Information It is a cytotoxic agent or antimetabolite and it is toxic to living cells, especially to certain cancer or precancerous cells. It destroys sun-damaged skin ...

9. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK549808/

Fluorouracil - StatPearls - NCBI Bookshelf [1] Randomized clinical trials have shown that chemoprevention therapy with 5% topical fluorouracil has reduced the incidence of squamous cell carcinomas in ...