Immunotherapy + Prednisone + Sirolimus for Skin Cancer

Recruiting at 24 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Sirolimus, Prednisone

Must not be taking: Investigational agents, Treatment-dose steroids

Disqualifiers: Liver transplant, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 25

Duration: 96 weeks

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests the combination of nivolumab and ipilimumab with sirolimus and prednisone for the treatment of skin (cutaneous) cancer that cannot be removed by surgery (unresectable) or that has spread from where it first started to other places in the body (metastatic) in kidney transplant recipients. Immunotherapy with nivolumab and ipilimumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Sirolimus and prednisone are immunosuppressants that are given to keep the body from rejecting the transplanted kidney. Giving nivolumab and ipilimumab in combination with sirolimus and prednisone may kill more cancer cells, while also keeping the transplanted kidney healthy, in patients with unresectable or metastatic cutaneous cancer who have received a kidney transplant.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you must not be receiving any other investigational agents and should have recovered from significant side effects of recent treatments before enrolling.

What data supports the effectiveness of the drug Sirolimus for skin cancer?

Research shows that Sirolimus, an immunosuppressant, may help prevent the growth of skin tumors in patients with a high risk of skin cancer, such as those who have had kidney transplants. It has been found to stop or even reverse the progression of pre-cancerous skin conditions. ^{1 2 3 4 5}

Is the combination of Immunotherapy, Prednisone, and Sirolimus generally safe for humans?

Immunotherapy drugs like Ipilimumab and Nivolumab can cause immune-related side effects in about 6.2% of patients, which are usually manageable and not fatal. Sirolimus, used in organ transplants, can increase lipid levels and has been linked to skin issues like rashes, but it generally has a lower risk of serious complications compared to other immunosuppressants. ^{3 5 6 7 8}

What makes the drug combination of Ipilimumab, Nivolumab, Prednisone, and Sirolimus unique for treating skin cancer?

This drug combination is unique because it includes Sirolimus, which has shown potential in preventing and inhibiting the progression of skin cancer due to its immunosuppressive and anti-proliferative properties, unlike traditional treatments that may not target these pathways. ^{1 2 3 5 9}

Research Team

Evan Lipson, MD

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Eligibility Criteria

This trial is for adult kidney transplant recipients with a functioning graft, who have skin cancer that's either inoperable or has spread. They should not need dialysis and must have had certain prior treatments if they have specific types of skin cancer like Basal cell carcinoma or BRAF-mutant melanoma.

Inclusion Criteria

I have had treatments targeting the hedgehog pathway for my basal cell carcinoma.

I have a tumor that can be measured with scans or X-rays.

Your white blood cell count is at least 2,000 per microliter.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Treatment

Participants receive sirolimus and prednisone orally daily, starting 7 days prior to cycle 1 day 1 of immunotherapy

1 week

Treatment

Participants receive nivolumab and ipilimumab intravenously, with tumor response assessment 6 weeks after the first dose. Cycles repeat every 4 weeks for a total of 24 cycles in the absence of disease progression or unacceptable toxicity

96 weeks

24 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up every 12 weeks for 1 year, then every 16 weeks for the second year, and every 20 weeks for up to 5 years

5 years

Multiple visits (in-person)

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Prednisone
• Sirolimus

Trial Overview The study tests nivolumab and ipilimumab (immunotherapies) combined with sirolimus and prednisone (immunosuppressants). This mix aims to fight the skin cancer while protecting the transplanted kidney from being rejected by the body.

Participant Groups

Group I: Treatment (nivolumab and ipilimumab) Experimental Treatment 9 Interventions

See detailed description

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 44 renal transplant recipients, switching to sirolimus-based immunosuppression significantly halted the progression and even regressed preexisting skin premalignancies within 6 months, with continued improvement at 12 months.

The incidence of new nonmelanoma skin cancers (NMSC) was much lower in the sirolimus group, with only one case compared to eight in the control group, highlighting sirolimus's potential to enhance skin cancer prevention in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. Salgo, R., Gossmann, J., Schöfer, H., et al.[2023]

A meta-analysis of 5 randomized trials with 1499 kidney transplant patients found that sirolimus-based immunosuppression significantly reduces the risk of non-melanoma skin cancer (NMSC) by nearly 51%.

Specifically, sirolimus was shown to lower the risk of both squamous-cell carcinoma and basal-cell carcinoma, indicating its potential antitumoral effects in kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus and non-melanoma skin cancer prevention after kidney transplantation: a meta-analysis. Gu, YH., Du, JX., Ma, ML.[2021]

Sirolimus, an immunosuppressive drug, can cause severe side effects like capillary leak syndrome, as observed in two psoriasis patients, highlighting the need for careful monitoring during treatment.

In one patient, skin analysis showed a significant increase in apoptotic cells in lesional skin after sirolimus treatment, suggesting that the drug may induce apoptosis in activated T cells, contributing to its adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic toxicity following administration of sirolimus (formerly rapamycin) for psoriasis: association of capillary leak syndrome with apoptosis of lesional lymphocytes. Kaplan, MJ., Ellis, CN., Bata-Csorgo, Z., et al.[2019]

Topically applied sirolimus significantly reduced clinical scores in patients with chronic plaque psoriasis, indicating its efficacy as a treatment option, with a mean score of 9.1 compared to 11.2 in the control group (P = 0.03).

The treatment also led to a significant decrease in CD4+ cells and proliferating cells in the skin, suggesting that sirolimus may exert its effects through immunosuppressive mechanisms, although improvements in plaque thickness and erythema were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial. Ormerod, AD., Shah, SA., Copeland, P., et al.[2013]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

In a study of 406 skin cancer patients treated with immune checkpoint inhibitors, 44.6% experienced immune-related adverse events (irAEs), with 10.9% classified as severe (sr) or serious (sd).

Most severe irAEs were treated with systemic steroids, and while 60% resolved, 28% had lasting effects, highlighting the need for careful management and the challenges in choosing second-line therapies, as none of the irAEs were fatal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors. Tomsitz, D., Ruf, T., Zierold, S., et al.[2023]

Sirolimus (RAPA) treatment in renal transplant patients significantly increases plasma triglyceride levels and VLDL-apoB100 concentrations due to a reduced catabolic rate of these lipoproteins, rather than increased production.

The study found that RAPA-induced hyperlipidemia is linked to decreased clearance of apoB100-containing lipoproteins, highlighting a metabolic pathway that could be targeted to manage lipid levels in patients undergoing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. Hoogeveen, RC., Ballantyne, CM., Pownall, HJ., et al.[2019]

A study of 13 patients receiving mTOR inhibitors (everolimus and temsirolimus) revealed that most dermatologic adverse events were mild to moderate, with 31% experiencing grade 1 and 54% grade 2 rashes, primarily affecting the trunk and extremities.

The predominant skin lesions were erythematous papules and pustules, with a common histopathologic finding of mixed spongiotic interface and perivascular dermatitis, indicating a need for further research into the specific skin reactions caused by these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and histopathologic characteristics of rash in cancer patients treated with mammalian target of rapamycin inhibitors. Balagula, Y., Rosen, A., Tan, BH., et al.[2022]

In a study using human skin models and hairless mice, rapamycin increased apoptosis in response to UV exposure, while cyclosporine decreased it, indicating that different immunosuppressants have varying local effects on skin cancer risk.

Surprisingly, high doses of immunosuppressants did not accelerate tumor development in mice, and cyclosporine even delayed tumor onset, suggesting that factors other than immunosuppressive drugs contribute to the increased skin cancer risk in organ transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary immunosuppressants do not enhance UV-induced skin carcinogenesis, and reveal discordance between p53-mutant early clones and carcinomas. Voskamp, P., Bodmann, CA., Koehl, GE., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. [2023]

2. Thailand pubmed.ncbi.nlm.nih.gov

Sirolimus and non-melanoma skin cancer prevention after kidney transplantation: a meta-analysis. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Systemic toxicity following administration of sirolimus (formerly rapamycin) for psoriasis: association of capillary leak syndrome with apoptosis of lesional lymphocytes. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial. [2013]

5. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Clinical and histopathologic characteristics of rash in cancer patients treated with mammalian target of rapamycin inhibitors. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Dietary immunosuppressants do not enhance UV-induced skin carcinogenesis, and reveal discordance between p53-mutant early clones and carcinomas. [2013]