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Immunotherapy After Transplantation for Skin Cancer Prevention in Organ Transplant Recipients

Primary Purpose

Immunotherapy, Cutaneous Squamous Cell Carcinoma, Actinic Keratoses

Status

Not yet recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Calcipotriol Only Product in Cutaneous Dose Form

Vaseline

Topical 5FU

About this trial

This is an interventional treatment trial for Immunotherapy focused on measuring Squamous Cell Carcinoma, Actinic keratoses, Calcipotriol ointment, 5-FU cream, Prevention, Organ Transplant Recipients, Immunotherapy

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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).

Sites / Locations

Massachusetts General Hospital
Barnes-Jewish Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Topical Calcipotriol ointment plus 5-Fluorouracil cream

Topical vaseline plus 5-Fluorouracil 2.5% cream

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

The changes in baseline number of AKs on treated anatomical sites in post-transplant OTRs

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

The changes in the number of SCC on treated anatomical sites in post-transplant OTRs

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

The changes in the magnitude of TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates in in the AK and normal skin after transplantation

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.

The changes in immune infiltrate (CD3+, CD4+ and CD8+ TRM cell) in any SCC that develops 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.

Number of Participants with Treatment Related Adverse Events

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

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 erythema extent and intensity scores (0-4) of the treated anatomical sites

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)

The changes in response to treatment (AKs number) between treated anatomical sites

The changes in response to topical calcipotriol plus 5-FU versus Vaseline plus 5-FU between treated anatomical sites

The changes in SCC prevention (number of SCC) on the untreated anatomical sites (i.e., trunk and lower extremities) of OTRs

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.

Full Information

NCT ID

NCT04642287

First Posted

November 4, 2020

Last Updated

March 22, 2023

Sponsor

Massachusetts General Hospital

Collaborators

Washington University School of Medicine

1. Study Identification

Unique Protocol Identification Number

NCT04642287

Brief Title

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

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

January 2026 (Anticipated)

Primary Completion Date

January 2029 (Anticipated)

Study Completion Date

January 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

Collaborators

Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

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.

Allocation

Randomized

Enrollment

64 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Topical Calcipotriol ointment plus 5-Fluorouracil cream

Arm Type

Experimental

Arm Description

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.

Arm Title

Topical vaseline plus 5-Fluorouracil 2.5% cream

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Calcipotriol Only Product in Cutaneous Dose Form

Other Intervention Name(s)

Topical Calcipotriene ointment

Intervention Description

Calcipotriene is a form of vitamin D. It works by inducing thymic stromal lymphopoietin cytokine expression in the skin.

Intervention Type

Drug

Intervention Name(s)

Vaseline

Other Intervention Name(s)

Petrolatum

Intervention Description

Placebo

Intervention Type

Drug

Intervention Name(s)

Topical 5FU

Other Intervention Name(s)

Topical 5-fluorouracil

Intervention Description

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

Primary Outcome Measure Information:

Title

The changes in baseline number of AKs on treated anatomical sites in post-transplant OTRs

Description

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

Time Frame

8 weeks after treatment

Secondary Outcome Measure Information:

Title

The changes in the number of SCC on treated anatomical sites in post-transplant OTRs

Description

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

Time Frame

1, 2 and 4 years after treatment

Title

The changes in the magnitude of TSLP, CD3+, CD4+ and CD8+ TRM cell infiltrates in in the AK and normal skin after transplantation

Description

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.

Time Frame

at one day after 6-day treatment and at one year post-treatment

Title

The changes in immune infiltrate (CD3+, CD4+ and CD8+ TRM cell) in any SCC that develops after treatment

Description

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.

Time Frame

up to 4 years after treatment

Title

Number of Participants with Treatment Related Adverse Events

Description

Adverse events will be assessed including any local skin reactions like itching and rash

Time Frame

From the start of treatment until 30 days after the end of treatment, up to 2 months

Title

Number of participants with any proven rejection of the graft in OTRs

Description

Number of participants with any biopsy proven acute rejection of the graft after treatment with calcipotriol plus 5-FU compared to test group.

Time Frame

From the start of treatment until 30 days after the end of treatment

Title

The changes in erythema extent and intensity scores (0-4) of the treated anatomical sites

Description

Time Frame

at one day after the completion of a 6-day treatment

Title

The changes in response to treatment (AKs number) between treated anatomical sites

Description

The changes in response to topical calcipotriol plus 5-FU versus Vaseline plus 5-FU between treated anatomical sites

Time Frame

at one day after treatment and one year after treatment

Title

The changes in SCC prevention (number of SCC) on the untreated anatomical sites (i.e., trunk and lower extremities) of OTRs

Description

Time Frame

at one, two and four years post-transplant.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

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).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Shadmehr Demehri, MD/ PHD

Phone

617-643-6436

sdemehri1@mgh.harvard.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Marjan Azin, MD

Phone

617-724-7897

mazin@mgh.harvard.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shadmehr Demehri, MD/PHD

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Shadmehr Demehri, MD

Phone

617-643-6436

sdemehri1@mgh.harvard.edu

First Name & Middle Initial & Last Name & Degree

Marjan Azin, MD

Phone

617-724-7897

mazin@mgh.harvard.edu

Facility Name

Barnes-Jewish Hospital

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63108

Country

United States

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Milan J Anadkat, MD

Phone

314-362-2643

manadkat@dom.wustl.edu

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

27869649

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.

Results Reference

background

PubMed Identifier

30895944

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.

Results Reference

background

Learn more about this trial

Immunotherapy After Transplantation for Skin Cancer Prevention in Organ Transplant Recipients

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