Clinical trial NCT04642287: Immunotherapy After Transplantation for Skin Cancer Prevention in Organ Transplant Recipients
Official title: Calcipotriol Plus 5-Fluorouracil Immunotherapy for Skin Cancer Prevention in Organ Transplant Recipients
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Immunotherapy
Cutaneous Squamous Cell Carcinoma
Actinic Keratoses
Organ Transplant Recipients
Skin Cancer
Keywords: Squamous Cell Carcinoma
Actinic keratoses
Calcipotriol ointment
5-FU cream
Prevention
Organ Transplant Recipients
Immunotherapy
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Washington University School of Medicine
First posted: 2020-11-24
Enrollment: 0
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: This clinical trial aims to investigate the efficacy of Calcipotriol ointment combined with 5-FU cream in Organ Transplant Recipients (OTRs) to determine if it can stimulate the immune cells against actinic keratoses precancerous skin lesions after transplantation and prevent cutaneous squamous cell carcinoma (SCC) in long-term.

Detailed description: The main goal of this investigator-initiated clinical trial is to determine the efficacy of topical calcipotriol combined with 5-fluorouracil (5-FU) treatment in OTRs on immunosuppressive medications with precancerous skin lesions called actinic keratoses (AKs) and a history of non-melanoma skin cancer in order to eliminate AKs and prevent squamous cell carcinoma (SCC) development. SCC is the most common cutaneous malignancy seen after transplantation, with a 65-250fold 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. Our previous findings have established the efficacy of calcipotriol in combination with 5-FU in inducing an antitumor immunity against AKs 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 FDA-approved low calcemic vitamin D analogue for the treatment of psoriasis. Topical 5-FU is a standard chemotherapy for AKs. Based on our previous findings demonstrating the synergistic impact of TSLP induction by calcipotriol in combination with the cytotoxic effects of 5-FU that leads to a robust T cell immunity against early skin carcinogenesis in immunocompetent patients, we aim to determine whether this efficacy is maintained in OTRs on immunosuppressive therapy and its effect on SCC prevention in long-term after transplantation.

Eligibility criteria: Inclusion Criteria:

* Solid organ transplant recipients with AKs and a history of non-melanoma skin cancer in one year prior to enrollment into the study. The target population includes post-transplant OTRs.
* 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 baseline number of AKs on treated anatomical sites in post-transplant OTRs
timeFrame: 8 weeks after treatment
Secondary outcomes:
measure: The changes in the number of SCC on treated anatomical sites in post-transplant OTRs
timeFrame: 1, 2 and 4 years after treatment
measure: The changes in the magnitude of TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates in in the AK and normal skin after transplantation
timeFrame: at one day after 6-day treatment and at one year post-treatment
measure: The changes in immune infiltrate (CD3+, CD4+ and CD8+ TRM cell) in any SCC that develops after treatment
timeFrame: up to 4 years after 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 erythema extent and intensity scores (0-4) of the treated anatomical sites
timeFrame: at one day after the completion of a 6-day treatment
measure: The changes in response to treatment (AKs number) between treated anatomical sites
timeFrame: at one day after treatment and one year after treatment
measure: The changes in SCC prevention (number of SCC) on the untreated anatomical sites (i.e., trunk and lower extremities) of OTRs
timeFrame: at one, two and four years post-transplant.
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.