Immunotherapy + Prednisone + Sirolimus for Skin Cancer

Recruiting at 31 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for skin cancer that cannot be surgically removed or has spread, specifically in individuals who have had a kidney transplant. It combines two immunotherapy drugs, nivolumab and ipilimumab, which help the immune system fight cancer, with sirolimus (an immunosuppressant) and prednisone (a corticosteroid), used to protect the transplanted kidney. The goal is to determine if this combination can kill more cancer cells while maintaining kidney health. The trial seeks participants who have had a kidney transplant and have a type of skin cancer that cannot be treated with standard surgery or other therapies. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that the combination of nivolumab and ipilimumab is generally well-tolerated. Long-term research in people with skin cancer suggests these drugs can significantly improve survival rates. However, they can also cause side effects, such as fatigue, skin rash, and diarrhea. Serious side effects are less common but can occur.

Sirolimus and prednisone are approved to help prevent organ rejection in transplant patients and are generally considered safe for this use. Sirolimus may cause side effects like mouth sores and high blood pressure, while prednisone can lead to weight gain and mood changes.

This trial's combination aims to balance cancer treatment with protecting the transplanted kidney. While each treatment carries risks, their known safety profiles guide their combined use in this research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of immunotherapy drugs, Ipilimumab and Nivolumab, with Prednisone and Sirolimus for treating skin cancer because this approach takes a unique angle by combining powerful immune checkpoint inhibitors with supportive agents. Unlike traditional treatments like surgery, radiation, or chemotherapy, which directly target cancer cells, Ipilimumab and Nivolumab boost the body's immune system to fight cancer more effectively. The addition of Sirolimus, an immunosuppressant, is intriguing as it may help modulate the immune response to enhance the effectiveness of the treatment, while Prednisone can help manage inflammation and side effects. This combination aims to offer a more comprehensive attack on cancer cells, potentially improving outcomes for patients with advanced skin cancer.

What evidence suggests that this trial's treatments could be effective for skin cancer?

Research shows that using nivolumab and ipilimumab together can effectively treat advanced melanoma, a type of skin cancer. In one study, 59% of patients who received this combination survived, with a 45% lower chance of their cancer worsening compared to other treatments. Another study found that after 10 years, almost all patients who were alive and cancer-free at 3 years remained free of melanoma. These drugs help the immune system attack cancer cells. In this trial, participants will receive the combination of nivolumab and ipilimumab. Sirolimus and prednisone are included to protect kidney transplant patients by preventing organ rejection. This combination aims to treat cancer while keeping transplanted kidneys safe. ^{2 6 7 8 9}

Who Is on the Research Team?

Evan Lipson, MD

Principal Investigator

JHU Sidney Kimmel Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy-combination

Advanced Melanoma Skin Cancer | Clinical Trial Results 59% of those given OPDIVO® + YERVOY® for advanced melanoma survived, versus. In the clinical trial, people given OPDIVO + YERVOY had a 45% lower risk of ...

2. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2407417

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab ... Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e21541

Dual immunotherapy with nivolumab and ipilimumab for ... Stable disease (SD) occurred in 15.6%, while 38.5% experienced progression disease (PD). Median PFS for CR was not reached; for PR, it was 26.6 ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37058595/

5-Year Efficacy and Biomarker Results from CheckMate 238 Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) ...

5. news.bms.com news.bms.com/news/details/2019/Five-Year-Outcomes-for-Opdivo-nivolumab-in-Combination-with-Yervoy-ipilimumab-Demonstrate-Durable-Long-Term-Survival-Benefits-in-Patients-with-Advanced-Melanoma/default.aspx

Five-Year Outcomes for Opdivo (nivolumab) in ... Five-year overall survival rates were 52% for the Opdivo plus Yervoy combination, 44% for Opdivo alone, and 26% for Yervoy alone.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... Among these patients, 10-year overall survival rates were 86% with nivolumab-plus-ipilimumab, 85% with nivolumab, and 79% with ipilimumab ( ...

7. news.bms.com news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-Landmark-10-Year-Follow-Up-Data-from-CheckMate--067-Which-Showed-Continued-Durable-Long-Term-Survival-Benefit-with-Opdivo-plus-Yervoy-in-Advanced-Melanoma/default.aspx

067 Which Showed Continued Durable Long-Term ... With a minimum follow up of 10 years, median overall survival (OS) was 71.9 months with Opdivo plus Yervoy (95% CI: 38.2-114.4) - the longest ...

8. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy

Advanced Melanoma Skin Cancer | Clinical Trial Results In the clinical trial, people given OPDIVO had a 43% lower risk of their cancer spreading, growing, or getting worse than those given YERVOY alone. More people ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02229

Long-Term Outcomes With Nivolumab Plus Ipilimumab or ... Here, we report 6.5-year efficacy and safety outcomes. Patients and Methods. Patients with previously untreated unresectable stage III or stage ...