Pembrolizumab + Radiation Therapy for Melanoma

Overseen By George Ansstas, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Metastatic disease, Active autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 17

Duration: 12 months

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, single center, one cohort, non-randomized, phase II study. The aim is to evaluate the efficacy and safety of the combination of hypofractionated radiotherapy (HRT) and pembrolizumab on local tumor control in mucosal melanoma patients. Treatment effect will be compared with historical radiation therapy-alone control data.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on systemic steroid therapy or immunosuppressive therapy within 7 days before starting the study, except for up to 10 mg/day of prednisone or equivalent. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Pembrolizumab + Radiation Therapy for Melanoma?

Research shows that combining pembrolizumab (a drug that helps the immune system fight cancer) with hypofractionated radiotherapy (a type of radiation treatment given in larger doses over fewer sessions) can enhance the effectiveness of treatment in advanced melanoma patients, even those who previously did not respond to pembrolizumab alone. Some studies reported that this combination led to tumor shrinkage and improved survival rates in difficult-to-treat cases. ^{1 2 3 4 5}

Is the combination of pembrolizumab and radiation therapy safe for treating melanoma?

Pembrolizumab, also known as Keytruda, has been approved for treating melanoma and has shown some common side effects like fatigue, cough, and nausea. More serious immune-related side effects can include lung inflammation, liver inflammation, and thyroid issues. When combined with radiation therapy, it has been studied for safety in treating various cancers, including melanoma. ^{1 5 6 7 8}

How is the treatment of pembrolizumab combined with hypofractionated radiation therapy unique for melanoma?

This treatment is unique because it combines pembrolizumab, an immune-boosting drug that helps T cells attack cancer, with hypofractionated radiation therapy, which delivers higher doses of radiation in fewer sessions. This combination may enhance the immune response against melanoma, especially in difficult-to-treat cases, and could potentially lead to better outcomes than using either treatment alone. ^{1 2 8 9 10}

Research Team

George Ansstas, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for adults with mucosal melanoma who've had surgery to remove it, have not had radiation in the affected area, and are generally healthy. They must understand the study and agree to use birth control. People with active autoimmune diseases, recent vaccines, certain infections or other cancers aren't eligible.

Inclusion Criteria

I am 16 years old or older.

I am mostly self-sufficient and can carry out daily activities.

Your total bilirubin level is not more than 1.5 times the upper limit of normal at the institution where you are being treated.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

People with HIV can join, but if their CD4+ T-cell counts are very low or if they had a serious infection related to AIDS in the past year, they can't join.

Pregnant and/or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab intravenously every 21 days for up to 12 months and hypofractionated radiation therapy during the first 2 cycles

12 months

17 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Treatment Details

Interventions

• Hypofractionated Radiation Therapy
• Pembrolizumab

Trial Overview The study tests how well pembrolizumab (a drug) works with hypofractionated radiation therapy on mucosal melanoma compared to older treatments using only radiation. It's an early-phase trial without random assignment of patients.

Participant Groups

Group I: Pembrolizumab + Hypofractionated radiation therapy Experimental Treatment 2 Interventions

* Pembrolizumab will be given intravenously over 30 minutes (-5/+10 minutes) at a dose of 200 mg on an outpatient basis on Day 1 of each 21-day cycle for a total of up to 12 months (17 cycles). * Hypofractionated radiation therapy may be given at any point during the first 2 cycles of pembrolizuimab. It should begin within 90 days of surgical resection. Intensity modulated radiation therapy (IMRT) or intensity modulated proton therapy (IMPT) are to be used exclusively. IMRT or IMPT will be delivered twice per week in five fractions of 6 Gy given over 2.5 weeks totaling 30 Gy.

Hypofractionated Radiation Therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Approved in European Union as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Approved in Canada as Hypofractionated Radiotherapy for:

• Soft tissue sarcoma
• Extremity soft tissue sarcoma

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

In a phase I trial involving 24 patients with metastatic cancers, the combination of pembrolizumab and hypofractionated radiotherapy (HFRT) was well tolerated, with 83% experiencing only mild treatment-related adverse events and no severe toxicities.

The treatment showed promising efficacy, particularly in patients with NSCLC or melanoma who had previously progressed on anti-PD-1 therapy, with some achieving prolonged responses of up to 28.1 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours. Maity, A., Mick, R., Huang, AC., et al.[2022]

In a study of 25 advanced melanoma patients treated with both radiotherapy and anti-PD-1 therapy, hypo-fractionated radiotherapy showed promising results, with 24% of radiated lesions achieving a complete response and 12% a partial response.

The study suggests a potential 'abscopal effect,' where responses in non-radiated lesions were correlated with those in radiated lesions, indicating that radiotherapy may enhance the overall efficacy of anti-PD-1 therapy without unusual adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients. Roger, A., Finet, A., Boru, B., et al.[2021]

A 53-year-old male with metastatic melanoma showed complete resolution of a large neck mass after receiving a single high-dose GRID radiation therapy (20 Gy) combined with pembrolizumab, demonstrating the potential efficacy of this treatment approach.

The case suggests that high-dose GRID radiation can enhance the immune response to immunotherapy, as evidenced by the patient's rapid and durable results without lasting side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Radiation as a Dramatic, Immunological Primer in Locally Advanced Melanoma. Mohiuddin, M., Park, H., Hallmeyer, S., et al.[2020]

In a study of 133 advanced melanoma patients who had previously failed anti-PD-1 therapy, adding hypofractionated radiotherapy to the treatment resulted in a 31% complete response rate and a 35% abscopal effect, indicating potential enhanced efficacy of the anti-PD-1 therapy.

The median progression-free survival was 15.2 months and melanoma-specific survival was 35.3 months, suggesting that this combination treatment may provide significant benefits, although the study's retrospective nature and small sample size highlight the need for further controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy. Funck-Brentano, E., Baghad, B., Fort, M., et al.[2021]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a study of 21 melanoma patients with brain metastases treated with concurrent pembrolizumab and radiation therapy, the treatment was found to be safe, with no severe toxicities reported, although one patient experienced Grade 3 side effects.

The use of stereotactic radiosurgery (SRS) alongside pembrolizumab resulted in a high response rate, with 70% of patients showing complete or partial responses at the first follow-up MRI, which is significantly better than response rates seen with SRS combined with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. Anderson, ES., Postow, MA., Wolchok, JD., et al.[2022]

The combination of pembrolizumab, hypofractionated stereotactic irradiation (HFSRT), and bevacizumab was found to be generally safe and well tolerated in 32 patients with recurrent high-grade gliomas, with manageable treatment-related adverse events such as proteinuria and fatigue.

In the bevacizumab-naïve group, 83% of patients showed a complete or partial response, with a median overall survival of 13.45 months, indicating promising preliminary efficacy of this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. Sahebjam, S., Forsyth, PA., Tran, ND., et al.[2021]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with metastatic solid tumours. [2022]

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

Efficacy of combined hypo-fractionated radiotherapy and anti-PD-1 monotherapy in difficult-to-treat advanced melanoma patients. [2021]

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

High-Dose Radiation as a Dramatic, Immunological Primer in Locally Advanced Melanoma. [2020]

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

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy. [2021]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]