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Immunotherapy After Transplantation for Skin Cancer Prevention in Organ Transplant Recipients

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ClinicalTrials.gov Identifier: NCT04642287
Recruitment Status : Not yet recruiting
First Posted : November 24, 2020
Last Update Posted : April 7, 2022
Sponsor:
Collaborator:
Washington University School of Medicine
Information provided by (Responsible Party):
Shadmehr Demehri, Massachusetts General Hospital

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.

Condition or disease Intervention/treatment Phase
Immunotherapy Cutaneous Squamous Cell Carcinoma Actinic Keratoses Organ Transplant Recipients Skin Cancer Drug: Calcipotriol Only Product in Cutaneous Dose Form Drug: Vaseline Drug: Topical 5FU Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: All participants, care giver and investigators measuring or analyzing the experimental data will be blinded to the interventions. Tissue samples collected will be labeled with 3-digit unique IDs and de-identified before studying in PI's lab. The study investigator will collect AK/skin samples and label them based on the study ID (e.g. "201") without compromising their blinded status. All the study records/photographs will be kept in a locked office or password-protected computer that is only accessible by the members of the research team.
Primary Purpose: Treatment
Official Title: Calcipotriol Plus 5-Fluorouracil Immunotherapy for Skin Cancer Prevention in Organ Transplant Recipients
Estimated Study Start Date : January 2023
Estimated Primary Completion Date : January 2026
Estimated Study Completion Date : January 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Calcipotriol Only Product in Cutaneous Dose Form
Calcipotriene is a form of vitamin D. It works by inducing thymic stromal lymphopoietin cytokine expression in the skin.
Other Name: Topical Calcipotriene ointment

Drug: Topical 5FU
5-FU is a chemotherapy that causes the death of proliferating tumor cells. Topical preparation of this drug is being used.
Other Name: Topical 5-fluorouracil

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.
Drug: Vaseline
Placebo
Other Name: Petrolatum

Drug: Topical 5FU
5-FU is a chemotherapy that causes the death of proliferating tumor cells. Topical preparation of this drug is being used.
Other Name: Topical 5-fluorouracil




Primary Outcome Measures :
  1. The changes in baseline number of AKs on treated anatomical sites in post-transplant OTRs [ Time Frame: 8 weeks after treatment ]
    The changes in baseline number of AKs on treated anatomical sites in post-transplant OTRs quantified based on participants' medical records and photographs in test versus control group


Secondary Outcome Measures :
  1. The changes in the number of SCC on treated anatomical sites in post-transplant OTRs [ Time Frame: 1, 2 and 4 years after treatment ]
    The changes in number of SCC on treated anatomical sites in post-transplant OTRs quantified based on participants' medical records, photographs and pathology results in test versus control group

  2. The changes in the magnitude of TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates in in the AK and normal skin after transplantation [ Time Frame: at one day after 6-day treatment and at one year post-treatment ]
    The changes in the magnitude of TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates in OTRs after transplantation compared to before transplantation in test versus control group.

  3. The changes in immune infiltrate (CD3+, CD4+ and CD8+ TRM cell) in any SCC that develops after treatment [ Time Frame: up to 4 years after treatment ]
    The changes in immune infiltrate in any SCC that develops after calcipotriol plus 5-FU versus Vaseline plus 5-FU treatment for up to 4 years post-transplant.

  4. 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

  5. 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.

  6. The changes in erythema extent and intensity scores (0-4) 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 in test versus control group in post-transplant OTRs. Treated skin will be evaluated for any sign of irritation including erythema, crusting or ulceration using a clinical erythema scale. (No erythema=0, mild erythema=1, sever erythema with minimal scaling=2, sever erythema with significant scaling=3, sever erythema with scaling, crusting, itching and burning=4)

  7. The changes in response to treatment (AKs number) between treated anatomical sites [ Time Frame: at one day after treatment and one year after treatment ]
    The changes in response to topical calcipotriol plus 5-FU versus Vaseline plus 5-FU between treated anatomical sites

  8. The changes in SCC prevention (number of SCC) 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.



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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04642287


Contacts
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Contact: Shadmehr Demehri, MD/ PHD 617-643-6436 sdemehri1@mgh.harvard.edu
Contact: Marjan Azin, MD 617-724-7897 mazin@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02215
Contact: Shadmehr Demehri, MD    617-643-6436    sdemehri1@mgh.harvard.edu   
Contact: Marjan Azin, MD    617-724-7897    mazin@mgh.harvard.edu   
United States, Missouri
Barnes-Jewish Hospital
Saint Louis, Missouri, United States, 63108
Contact: Milan J Anadkat, MD    314-362-2643    manadkat@dom.wustl.edu   
Sponsors and Collaborators
Massachusetts General Hospital
Washington University School of Medicine
Investigators
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Principal Investigator: Shadmehr Demehri, MD/PHD Massachusetts General Hospital
Publications:
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Responsible Party: Shadmehr Demehri, MD, PHD, Assistant Professor in Dermatology, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04642287    
Other Study ID Numbers: 2020P001220
First Posted: November 24, 2020    Key Record Dates
Last Update Posted: April 7, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Shadmehr Demehri, Massachusetts General Hospital:
Squamous Cell Carcinoma
Actinic keratoses
Calcipotriol ointment
5-FU cream
Prevention
Organ Transplant Recipients
Immunotherapy
Additional relevant MeSH terms:
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Carcinoma, Squamous Cell
Keratosis, Actinic
Skin Neoplasms
Keratosis
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Skin Diseases
Precancerous Conditions
Neoplasms by Site
Fluorouracil
Calcipotriene
Petrolatum
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Dermatologic Agents
Emollients