Calcipotriene + 5-Fluorouracil for Actinic Keratosis

Recruiting at 4 trial locations

Overseen By Amy Selegue, BSN, MLS, CCRP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Arizona

Must be taking: Tacrolimus, MMF

Must not be taking: Voriconazole

Disqualifiers: Organ rejection, Cancer therapy, HIV, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

56 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop your current medications. However, it mentions that participants should not be on other investigational agents and should be on a stable immunosuppressive regimen without voriconazole.

What data supports the effectiveness of the drug Calcipotriene + 5-Fluorouracil for Actinic Keratosis?

Research shows that the combination of calcipotriol and 5-fluorouracil (5-FU) is effective in treating actinic keratosis (AK), which is a skin condition that can lead to squamous cell carcinoma (a type of skin cancer). Additionally, 5-FU alone is recognized as one of the most effective treatments for AK. ^{1 2 3 4 5}

Is the combination of Calcipotriene and 5-Fluorouracil safe for treating actinic keratosis?

The combination of Calcipotriene and 5-Fluorouracil has been studied for safety in treating actinic keratosis, with most side effects being mild to moderate, such as facial irritation. Fluorouracil alone has been shown to be safe in long-term studies, with only a small percentage of participants experiencing adverse effects beyond mild skin reactions. ^{1 6 7 8 9}

How is the drug calcipotriene plus 5-fluorouracil unique for treating actinic keratosis?

The combination of calcipotriene and 5-fluorouracil is unique because it acts as an immunotherapy, potentially enhancing the body's immune response to treat actinic keratosis, which is a precursor to skin cancer. This combination may offer a different mechanism compared to other treatments that primarily focus on direct destruction of the lesions. ^{1 2 6 10 11}

What is the purpose of this trial?

This phase IIA study evaluates the effects of calcipotriene plus 5- fluorouracil immunotherapy for skin cancer prevention in organ transplant recipients. Solid organ transplant recipients are at high risk of developing skin cancer. Actinic keratosis (AK), is a premalignant skin lesion that can progress to squamous cell skin cancer. In this study, solid organ transplant recipients with multiple AKs are treated with topical calcipotriene and 5-FU to evaluate how effective this therapy is against AKs and if this could lower their risk of skin cancer. Topical calcipotriene is a form of vitamin D and is used to treat psoriasis. Prior research reported immunomodulatory effects in the skin induced by topical calcipotriene. Topical 5- fluorouracil is a chemotherapy agent and is one of the therapy options for multiple AKs in specific clinical scenarios. Prior research indicates that topical calcipotriene used together with topical 5-FU was more effective in treating multiple AKs than 5-FU alone in individuals with healthy immune system. This study is investigating now if similar beneficial effects can be seen in immunosuppressed individuals who are solid organ transplant recipients.

Research Team

Shadmehr Demehri

Principal Investigator

University of Arizona Cancer Center - Prevention Research Clinic

Eligibility Criteria

This trial is for organ transplant recipients who've had a kidney or lung transplant at least 2 years ago, are stable, and have 4-15 visible precancerous skin lesions. Participants must be adults with good overall health and blood counts within specific ranges. Pregnant women, those with recent cancer treatments, uncontrolled illnesses, certain infections or allergies to the study drugs cannot join.

Inclusion Criteria

I had a kidney or lung transplant over 2 years ago and my transplant is stable.

Your white blood cell count is between 3,000 and 12,000 per microliter.

I have 4 to 15 visible skin lesions in a specific area of my body.

Exclusion Criteria

Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements

You have HIV.

You have had allergic reactions to similar medicines like calcipotriene and 5-FU.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive calcipotriene plus 5-fluorouracil cream topically twice a day for 6 consecutive days. A second course may be administered at week 8 if AKs persist.

8 weeks

Multiple visits for treatment and skin biopsies

Follow-up

Participants are monitored for safety, effectiveness, and persistence of immune cells in AKs after treatment

6 months

Regular follow-up visits

Long-term follow-up

Assessment of long-term outcomes such as new SCC diagnosis and immune cell persistence

Up to 2 years

Treatment Details

Interventions

• Calcipotriene
• Fluorouracil

Trial Overview The study tests if a cream combining calcipotriene (a vitamin D form) and chemotherapy agent 5-fluorouracil can activate immune cells against precancerous skin lesions to prevent skin cancer in organ transplant patients.

Participant Groups

Group I: Prevention (calcipotriene, fluorouracil) Experimental Treatment 3 Interventions

Participants receive calcipotriene plus fluorouracil cream topically BID for 6 consecutive days on study. Participants also undergo skin biopsies throughout the study. Patients who continue to experience AKs at week 8 may receive a second course of calcipotriene plus fluorouracil cream topically BID for 6 consecutive days on study.

Calcipotriene is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Dovonex for:

• Psoriasis

Approved in European Union as Daivonex for:

• Psoriasis

Approved in Canada as Psorcutan for:

• Psoriasis

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

A short 4-day treatment with topical calcipotriol plus 5-fluorouracil (5-FU) significantly reduced the incidence of squamous cell carcinoma (SCC) in participants over a 3-year follow-up, with only 7% developing SCC compared to 28% in the control group.

The treatment also induced a strong immune response, evidenced by the formation of tissue-resident memory T (Trm) cells in the skin, which correlated with better long-term protection against SCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention. Rosenberg, AR., Tabacchi, M., Ngo, KH., et al.[2020]

In a study of 98 adult patients with actinic keratosis, 4% 5-fluorouracil cream demonstrated high effectiveness, with 74.5% of patients showing complete improvement in lesions after 8 weeks.

The treatment had a favorable safety profile, with most patients reporting only mild to moderate burning and erythema, which resolved over time, and a 65.3% rate of no relapse at 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Experience With Topical 5-Fluorouracil 4% (40 mg/g) Cream for the Treatment of Actinic Keratosis. Briatico, G., Brancaccio, G., Scharf, C., et al.[2023]

The combination of fluorouracil and 0.5% triamcinolone acetonide cream is as effective as fluorouracil alone for treating actinic keratoses, while reducing the unpleasant irritation typically caused by fluorouracil.

Using a diluted (0.1%) triamcinolone acetonide cream does not effectively suppress inflammation, indicating that the success of fluorouracil treatment is not linked to inflammation levels, but rather to its chemotherapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninflammatory destruction of actinic keratoses by fluorouracil. Breza, T., Taylor, R., Eaglstein, WH.[2013]

In a study involving 12 patients with multiple actinic keratoses (AKs), a sequential treatment using Solaraze gel followed by Actikerall solution achieved complete clearance in 8 out of 10 male patients and all female patients, demonstrating high efficacy for treating AKs.

The treatment was well tolerated, with only minor side effects such as contact dermatitis in one case, indicating a favorable safety profile and significant improvement in patients' quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential treatment of multiple actinic keratoses with solaraze and actikerall. Dirschka, T., Lear, JT.[2021]

Calcipotriene (calcipotriol) is an effective topical treatment for psoriasis, showing comparable efficacy to other standard therapies.

While some patients may experience mild skin irritation, this side effect is generally manageable, allowing for the continuation of treatment after the irritation resolves.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of psoriasis with calcipotriol used as monotherapy. Ramsay, CA.[2014]

In a study involving 277 participants over 18 months, fluorouracil cream 0.5% was found to be safe and well-tolerated, with only 4 participants (7.4%) experiencing mild treatment-related adverse events.

The cream significantly reduced actinic keratosis (AK) lesions, achieving clearance rates of 39.8% on the face/anterior scalp and 79.1% on the lips after the first treatment cycle, with continued effectiveness observed during a second treatment cycle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil cream 0.5% for actinic keratoses on multiple body sites: an 18-month open-label study. Stough, D., Bucko, AD., Vamvakias, G., et al.[2013]

A study involving 177 patients demonstrated that a microsphere-based formulation of 0.5% fluorouracil cream is effective in treating actinic keratosis (AK), with significant improvements in lesion counts and clearance compared to a vehicle control.

The treatment was found to be safe, with most patients experiencing only mild to moderate facial irritation, and efficacy increased with longer treatment durations of 1, 2, or 4 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Weiss, J., Menter, A., Hevia, O., et al.[2013]

Topical diclofenac gel (3%) is a moderately effective treatment for actinic keratosis, but it is less effective than the first-line treatment, fluorouracil, especially in terms of lesion disappearance after one month.

While diclofenac gel has a lower intensity of local adverse effects compared to fluorouracil, it still presents common side effects like contact dermatitis and skin rash, and its effectiveness is limited, making it suitable primarily for patients who cannot tolerate fluorouracil or when other treatments fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical diclofenac: new preparation. Moderate efficacy in actinic keratosis. [2013]

Carac (5-fluorouracil 0.5% cream) is highly effective in treating actinic keratoses, showing a 52.9% total clearance rate after 4 weeks compared to only 1.6% with a placebo, based on a study of 384 participants.

The cream significantly reduces the number of AK lesions by 82.5% compared to 19.3% with the vehicle, although the most common side effect reported is facial irritation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. Gupta, AK., Weiss, JS., Jorizzo, JL.[2013]

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]

A 1-week treatment with microsponge-based fluorouracil cream 0.5% significantly reduced actinic keratoses (AK) lesions compared to a vehicle control, demonstrating its efficacy (P<.001) in a study involving 356 participants.

The treatment was well-tolerated, with no serious adverse events reported, and only mild to moderate skin irritations experienced, indicating it is a safe option for patients with AKs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-week treatment with once-daily fluorouracil cream 0.5% in participants with actinic keratoses. Menter, A., Vamvakias, G., Jorizzo, J.[2013]

References

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

Skin cancer precursor immunotherapy for squamous cell carcinoma prevention. [2020]

2. Austria pubmed.ncbi.nlm.nih.gov

Real-World Experience With Topical 5-Fluorouracil 4% (40 mg/g) Cream for the Treatment of Actinic Keratosis. [2023]

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

Noninflammatory destruction of actinic keratoses by fluorouracil. [2013]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Sequential treatment of multiple actinic keratoses with solaraze and actikerall. [2021]

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

Management of psoriasis with calcipotriol used as monotherapy. [2014]

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

Fluorouracil cream 0.5% for actinic keratoses on multiple body sites: an 18-month open-label study. [2013]

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

Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. [2013]

8. France pubmed.ncbi.nlm.nih.gov

Topical diclofenac: new preparation. Moderate efficacy in actinic keratosis. [2013]

9. Canada pubmed.ncbi.nlm.nih.gov

5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp. [2013]

10. Switzerland 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. [2020]

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

One-week treatment with once-daily fluorouracil cream 0.5% in participants with actinic keratoses. [2013]