Pembrolizumab + Radiotherapy for Sarcoma

Overseen By University of California Irvine Medical

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of California, Irvine

Must be taking: Checkpoint inhibitors

Must not be taking: Immunosuppressants, Monoclonal antibodies

Disqualifiers: Pregnancy, Active autoimmune disease, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 weeks

9 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination treatment of pembrolizumab (a type of immunotherapy) and radiation therapy for individuals with advanced soft-tissue sarcoma, a cancer that begins in the body's soft tissues like fat or muscle. Researchers aim to determine if these treatments can work effectively together for patients whose cancer has spread or returned after previous treatment. The study tests two approaches: one combines pembrolizumab with radiation, and the other uses radiation alone or with existing immunotherapy. Individuals with advanced soft-tissue sarcoma that cannot be treated with surgery may be suitable candidates for this trial. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking cancer research.

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 must not be on active immunosuppression within 7 days before starting the treatment, and you cannot be receiving other investigational agents.

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

A previous study tested pembrolizumab, a type of immune therapy, in patients with advanced soft tissue and bone cancers. The study found it to be generally safe, though some patients experienced side effects like tiredness and skin rash. Research shows that pembrolizumab has been used in various types of cancer and is already FDA-approved for some conditions, indicating a known safety profile.

For stereotactic ablative radiotherapy (SBRT), studies have shown it to be generally safe and well-tolerated. It effectively controls tumors, even in patients who have undergone many treatments. Most side effects were mild, such as fatigue or skin changes.

Overall, past studies have shown both pembrolizumab and SBRT to be well-tolerated. While side effects can occur, they are usually mild to moderate. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab with radiotherapy for sarcoma because it leverages the immune system in a novel way. Unlike traditional treatments like surgery, chemotherapy, and standalone radiotherapy, pembrolizumab is a checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. The addition of radiotherapy may enhance this immune response by making cancer cells more visible to the immune system. This innovative approach could potentially improve treatment outcomes and offer a new hope for patients with sarcoma.

What evidence suggests that this trial's treatments could be effective for soft-tissue sarcoma?

Research has shown that pembrolizumab can help patients with soft-tissue sarcoma live longer without the disease returning. In this trial, one group of participants will receive pembrolizumab combined with radiation therapy. Studies have found that patients with advanced sarcoma who took pembrolizumab experienced better outcomes, including increased survival. Another group in this trial will receive radiation therapy, with or without standard of care checkpoint inhibitor immunotherapy. Stereotactic body radiation therapy (SBRT), a type of radiation treatment, has successfully controlled sarcoma tumors, with some patients experiencing long-lasting benefits. SBRT has demonstrated good results, such as high rates of tumor control and improved overall survival. Combining pembrolizumab with SBRT might enhance treatment effectiveness, based on their individual successes in past studies. ^{1 4 6 7 8}

Who Is on the Research Team?

Jeremy Harris, MD, MPhil

Principal Investigator

University of California, Irvine

Are You a Good Fit for This Trial?

Adults with advanced or recurrent soft-tissue sarcoma, not eligible for curative surgery. Must have measurable lesions, life expectancy over 3 months, and proper organ/marrow function. HIV-positive patients can join if viral load is undetectable. Excludes pregnant/nursing women, those on active immunosuppression, with recent chemotherapy/radiotherapy or other investigational agents.

Inclusion Criteria

I have HBV or HCV but my viral load is undetectable or I am on suppressive therapy.

My cancer is a type of sarcoma with a high number of mutations.

I haven't taken any immunosuppressive drugs in the last week.

Exclusion Criteria

My condition can potentially be cured with surgery.

I have another cancer besides skin cancer that is getting worse or needs treatment.

Patients who have not recovered from adverse events due to prior anti-cancer therapy administered

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab 400 mg intravenously every 42 days and radiation therapy in 1 to 10 fractions

6-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Long-term follow-up

Participants are monitored for progression-free survival and overall survival

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Stereotactic Body Radiation Therapy

Trial Overview The trial tests the combination of pembrolizumab (an immunotherapy drug) and stereotactic ablative radiotherapy (SBRT) in treating metastatic sarcoma. It aims to see if this combo is feasible for patients who've had previous systemic therapy or are ineligible for it.

How Is the Trial Designed?

Group I: B: Radiation Therapy with or without standard of care checkpoint inhibitor immunotherapy Experimental Treatment 1 Intervention

Patients who are currently receiving a checkpoint inhibitor immunotherapy regimen will be allowed to continue their regimen at their treating oncologist's discretion. Radiation therapy will be delivered in 1 to 10 fractions starting on Day 1.

Group II: A: Pembrolizumab + Radiation Therapy Experimental Treatment 2 Interventions

Patients receive pembrolizumab 400 mg intravenous every 42 days; Radiation therapy in 1 to 10 fractions.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

University of California, Irvine

Lead Sponsor

Trials

580

Recruited

4,943,000+

Published Research Related to This Trial

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, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

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]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

Pembrolizumab, an immunotherapy targeting PD-1, showed limited effectiveness in a patient with metastatic renal cell carcinoma, highlighting that only 20-40% of patients benefit from such treatments due to individual tumor biology and immune checkpoint diversity.

The patient's rapid disease progression during treatment may be linked to a lack of tumor-infiltrating lymphocytes (TILs) and the specific radiation dose and schedule used, which could affect the tumor microenvironment and the potential synergy with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Alexander, GS., Palmer, JD., Tuluc, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a phase 2 study involving 86 patients with advanced soft-tissue or bone sarcoma, pembrolizumab demonstrated some efficacy, particularly in undifferentiated pleomorphic sarcoma (40% response rate) and dedifferentiated liposarcoma (20% response rate), although the overall response rate did not meet the primary endpoint.

The treatment was associated with some serious adverse events, including immune-related conditions like adrenal insufficiency and pneumonitis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Tawbi, HA., Burgess, M., Bolejack, V., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a phase 2 trial involving 12 patients with advanced osteosarcoma, pembrolizumab showed no clinical benefit at 18 weeks, with all patients experiencing disease progression and a median overall survival of only 6.6 months.

Despite the lack of significant antitumor activity, pembrolizumab was well-tolerated, with no treatment-related deaths or severe adverse events, suggesting it may be safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial. Boye, K., Longhi, A., Guren, T., et al.[2022]

Pembrolizumab, a monoclonal antibody targeting PD-1, showed significant efficacy in treating a 79-year-old patient with advanced squamous cell lung cancer, leading to a complete response after just 3 cycles of treatment.

However, the patient developed acute myelomonocytic leukemia after starting pembrolizumab, highlighting a potential safety concern that warrants further investigation into the drug's effects on blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. Kim, HB., Park, SG., Hong, R., et al.[2020]

Citations

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Immunotherapy Drug Pembrolizumab Improves Outcomes ... “Based on our finding that pembrolizumab significantly improved disease-free survival, we hope that more clinicians will start incorporating ...

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Safety and efficacy of pembrolizumab, radiation therapy ... The trial showed a clinically meaningful improvement in disease-free survival with addition of preoperative and postoperative pembrolizumab to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11236331/

Long Duration Pembrolizumab for Metastatic ... This report is unique owing to the probable longest reporting of successful continuous immunotherapy for metastatic UPS over 6.5 years and 109 cycles.

4. cancerletter.com cancerletter.com/clinical-roundup/20241115_7d/

Keytruda improves outcomes in soft tissue sarcoma Keytruda to standard of care for patients with advanced soft tissue sarcoma of the limb significantly improved disease-free survival.

5. ascopubs.org ascopubs.org/doi/10.1200/EDBK_432234

Immunotherapy in Sarcoma: Current Data and Promising ... The SARC028 phase II clinical trial was the first to demonstrate efficacy of pembrolizumab (PD-1 inhibitor) in patients with either STS ( ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01295827

NCT01295827 | Study of Pembrolizumab (MK-3475) in ... The study will investigate the safety, tolerability, and efficacy of pembrolizumab (2 mg/kg and 10 mg/kg) in participants with advanced or metastatic MEL.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7939029/

Pembrolizumab in Advanced Soft Tissue and Bone Sarcomas We assessed pembrolizumab (P), an anti-PD-1 antibody, for safety and activity in patients with advanced soft tissue (STS) and bone (BS) sarcomas.

8. merck.com merck.com/news/ten-year-data-for-mercks-keytruda-pembrolizumab-demonstrates-sustained-overall-survival-benefit-versus-ipilimumab-in-advanced-melanoma/

Ten-Year Data for Merck's KEYTRUDA® (pembrolizumab ... At 10 years, more than one-third (34.0%) of patients with advanced melanoma were alive after treatment with KEYTRUDA, compared to 23.6% of patients treated ...