This clinical trial aims to investigate the efficacy of Calcipotriol ointment combined with 5-fluorouracil cream as an immunotherapy for actinic keratosis in Organ Transplant Recipients (OTRs) before transplantation and determine whether it can prevent cutaneous squamous cell carcinoma (SCC) in OTRs post-transplant.
Full Title of Study: “Calcipotriol Plus 5-Flourouracil Immunotherapy Before Transplantation for Skin Cancer Prevention in Organ Transplant Recipients”
- Study Type: Interventional
- Study Design
- Allocation: Randomized
- Intervention Model: Parallel Assignment
- Primary Purpose: Prevention
- Masking: Triple (Participant, Care Provider, Investigator)
- Study Primary Completion Date: June 2024
The main goal of this investigator-initiated clinical trial is to determine the efficacy of topical calcipotriol combined with 5-flourouracil (5-FU) treatment in organ transplant candidates with precancerous skin lesions called actinic keratoses (AKs) with a history of skin cancer in order to prevent squamous cell carcinoma (SCC) development after transplantation. SCC is the most common cutaneous malignancy seen after transplantation, with a 65-250 fold greater incidence in organ transplant recipients (OTRs) compared to the general population. This increased risk is due to the systemic immunosuppression caused by anti-rejection medications, which are indispensable for protecting against allograft loss. Previously, we have demonstrated the high efficacy of topical calcipotriol plus 5-FU immunotherapy for AKs on the face and scalp in significantly reducing the risk of SCC development within 3 years post-treatment in immunocompetent patients. This SCC risk reduction is accompanied by the induction of robust T cell immunity and TRM cell formation against AKs. Calcipotriol is a low calcemic vitamin D analogue that is FDA-approved for the treatment of psoriasis. Topical 5-FU is a chemotherapy that is the standard treatment for AKs. Our previous research demonstrates the synergistic impact of calcipotriol in combination with 5-FU on a robust T cell immunity against early skin carcinogenesis in immunocompetent patients. Therefore, we aim to determine the efficacy of this immunotherapy before transplantation in reducing the risk of SCC post-transplant despite the immunosuppressive medications.
- Drug: Calcipotriol Only Product in Cutaneous Dose Form
- Calcipotriol (Calcipotriene) is a form of vitamin D. It works by inducing thymic stromal lymphopoietin cytokine expression in the skin.
- Drug: Vaseline
- Drug: Topical 5FU
- 5-FU is a chemotherapy that causes the death of proliferating tumor cells. Topical preparation of this drug is being used.
Arms, Groups and Cohorts
- Experimental: Topical Calcipotriol ointment plus 5-Fluorouracil cream
- Topical Calcipotriol 0.0025% ointment plus 5-Fluorouracil 2.5% cream will be administered by the participants to their face, scalp and upper extremities twice a day for 6 consecutive days.
- Placebo Comparator: Topical vaseline plus 5-Fluorouracil 2.5% cream
- Topical Vaseline plus 5-Fluorouracil 2.5% cream will be administered by the participants to their face, scalp and upper extremities twice a day for 6 consecutive days.
Clinical Trial Outcome Measures
- The changes in the percentage of participants with new SCC on treated anatomical sites in OTRs
- Time Frame: Year 2 post-transplant
- The changes in the percentage of participants with new SCC on treated anatomical sites quantified based on participants’ medical records, photographs and pathology results after transplantation in test versus control group.
- The percent change in baseline number of AKs on the treated anatomical sites in OTRs.
- Time Frame: 8 weeks after treatment
- The percent change in baseline number of AKs on the treated anatomical sites in post-transplant OTRs quantified based on participants’ medical records and photographs after transplantation in test versus control group
- The changes in TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates and other immune factors/cells in the AK and normal skin
- Time Frame: at one day after 6-day treatment and at one year post-transplant.
- The changes in TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates and other immune factors/cells in the AK and normal skin in test versus control group after treatment and transplantation compared to before treatment.
- The changes in immune infiltrate in any SCC that develops after treatment
- Time Frame: for up to 4 years post-transplant
- The changes in immune infiltrate in any SCC that develops after calcipotriol plus 5-FU versus Vaseline plus 5-FU treatment
- The changes in SCC prevention (SCC number) on the untreated anatomical sites (i.e., trunk and lower extremities) of OTRs
- Time Frame: at one, two and four years post-transplant.
- The changes in efficacy of a twice daily 6-day treatment with topical calcipotriol plus 5-FU (test) versus Vaseline plus 5-FU (control) before transplantation in preventing SCC on the untreated anatomical sites (i.e., trunk and lower extremities) of OTRs.
- The changes in erythema extent and intensity scores of the treated anatomical sites
- Time Frame: at one day after the completion of a 6-day treatment.
- The changes in erythema extent and intensity scores of the treated anatomical sites after treatment in test versus control group. Treated skin will be evaluated for any sign of irritation including erythema, crusting or ulceration using a clinical erythema scale.
- Number of Participants with Treatment Related Adverse Events
- Time Frame: From the start of treatment until 30 days after the end of treatment, up to 2 months
- Adverse events will be assessed including any local skin reactions like itching and rash.
- Number of participants with any proven rejection of the graft in OTRs
- Time Frame: From the start of treatment until 30 days after the end of treatment
- Number of participants with any biopsy proven acute rejection of the graft after treatment with calcipotriol plus 5-FU compared to test group
- The changes in response to treatment (AK and SCC number) between treated anatomical sites
- Time Frame: at one day after treatment and one year after transplantation.
- The changes in response to topical calcipotriol plus 5-FU versus Vaseline plus 5-FU between treated anatomical sites
Participating in This Clinical Trial
- Solid organ transplant candidates with AKs and a history of non-melanoma skin cancer. The target population includes the patients who are undergoing kidney, lung, liver and heart transplantations.
- Presence of four to fifteen clinically typical, visible, and discrete AKs in 25 cm2 on any of the four anatomical sites: scalp, face, right upper extremity and left upper extremity.
- The period between the first visit and transplantation is minimum 4 weeks and maximum 12 months.
- Age of at least 18 years
- Ability and willingness of the patient to participate in the study (Informed consent will be obtained)
- Treatment area is within 5 cm of an incompletely healed wound or a suspected basal cell or squamous cell carcinoma.
- Treatment area contained hypertrophic and hyperkeratotic lesions, cutaneous horns, or lesions that had not responded to repeated cryotherapy.
- Patients with history of hypercalcemia or vitamin D toxicity.
- Female participants must be either of non-reproductive potential (i.e., post-menopausal by history of age > 50 years old and no menses for >1 year without an alternative medical cause; OR history of hysterectomy, history of bilateral tubal ligation, or history of bilateral oophorectomy) OR must have a negative serum pregnancy test within 7 days prior to study registration.
- Patients with DPD (Dihydropyrimidine Dehydrogenase) deficiency (due to their higher risk of 5-FU toxicity).
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Massachusetts General Hospital
- Provider of Information About this Clinical Study
- Principal Investigator: Shadmehr Demehri, MD, PHD – Massachusetts General Hospital
- Overall Contact(s)
- Shadmehr Demehri, MD, 617-643-6436, firstname.lastname@example.org
Cunningham TJ, Tabacchi M, Eliane JP, Tuchayi SM, Manivasagam S, Mirzaalian H, Turkoz A, Kopan R, Schaffer A, Saavedra AP, Wallendorf M, Cornelius LA, Demehri S. Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest. 2017 Jan 3;127(1):106-116. doi: 10.1172/JCI89820. Epub 2016 Nov 21.
Rosenberg AR, Tabacchi M, Ngo KH, Wallendorf M, Rosman IS, Cornelius LA, Demehri S. Skin cancer precursor immunotherapy for squamous cell carcinoma prevention. JCI Insight. 2019 Mar 21;4(6). pii: 125476. doi: 10.1172/jci.insight.125476. eCollection 2019 Mar 21.
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