Clinical trial NCT04329221: Immunotherapy Before Transplantation for Skin Cancer Prevention in Organ Transplant Recipients
Official title: Calcipotriol Plus 5-Flourouracil Immunotherapy Before Transplantation for Skin Cancer Prevention in Organ Transplant Recipients
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Cutaneous Squamous Cell Carcinoma
Actinic Keratoses
Skin Cancer
Organ Transplant Recipients
Immunotherapy
Keywords: Calcipotriol ointment
5-FU cream
Squamous Cell Carcinoma
Actinic Keratoses
Organ Transplant Recipients
Prevention
Immunotherapy
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Washington University School of Medicine
First posted: 2020-04-01
Enrollment: 0
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel assignment
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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)

Exclusion Criteria:

* 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).

Primary outcomes:
measure: The changes in the percentage of participants with new SCC on treated anatomical sites in OTRs
timeFrame: Year 2 post-transplant
Secondary outcomes:
measure: The percent change in baseline number of AKs on the treated anatomical sites in OTRs.
timeFrame: 8 weeks after treatment
measure: The changes in TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates and other immune factors/cells in the AK and normal skin
timeFrame: at one day after 6-day treatment and at one year post-transplant.
measure: The changes in immune infiltrate in any SCC that develops after treatment
timeFrame: for up to 4 years post-transplant
measure: The changes in SCC prevention (SCC number) on the untreated anatomical sites (i.e., trunk and lower extremities) of OTRs
timeFrame: at one, two and four years post-transplant.
measure: The changes in erythema extent and intensity scores of the treated anatomical sites
timeFrame: at one day after the completion of a 6-day treatment.
measure: Number of Participants with Treatment Related Adverse Events
timeFrame: From the start of treatment until 30 days after the end of treatment, up to 2 months
measure: Number of participants with any proven rejection of the graft in OTRs
timeFrame: From the start of treatment until 30 days after the end of treatment
measure: The changes in response to treatment (AK and SCC number) between treated anatomical sites
timeFrame: at one day after treatment and one year after transplantation.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
Study officials:
affiliation: Massachusetts General Hospital
name: Shadmehr Demehri, MD/PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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):e125476. doi: 10.1172/jci.insight.125476. eCollection 2019 Mar 21.