Pembrolizumab + SBRT for Advanced Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Active TB, CNS metastases, 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: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the safest way to combine stereotactic body radiotherapy (SBRT), a precise radiation treatment, with pembrolizumab, an immunotherapy drug, for people with advanced solid tumors. Researchers are determining the best radiation dose for different organs and assessing how this combination affects tumors. The trial seeks participants with advanced cancer who have limited treatment options, particularly those with a few cancer spots (four or fewer) or large tumors that can be partially treated. 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 innovative combination therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy at a dose greater than 10 mg of Prednisone daily, you may not be eligible to participate.

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

Research has shown that the combination of pembrolizumab and stereotactic body radiotherapy (SBRT) is generally well-tolerated. Some studies found that using pembrolizumab with SBRT had a manageable safety profile. Although specific side effects were not detailed, the treatment was considered acceptable in terms of safety.

Pembrolizumab alone has been studied in various cancers and has shown an 18% response rate in some cases. It is already FDA-approved for other conditions, indicating its well-established safety. However, using it with SBRT is newer, and this trial aims to explore the safety of this combination.

As this study is in an early phase, it primarily focuses on assessing safety and determining the optimal radiation dose to use with pembrolizumab. There is still much to learn about how people react to this treatment mix. Participants may experience side effects, but the study will help identify the safest doses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about these treatments because they combine pembrolizumab with stereotactic body radiotherapy (SBRT), offering a potentially more precise and effective approach for advanced cancer. Pembrolizumab is an immunotherapy drug that unleashes the immune system to attack cancer cells, while SBRT delivers high doses of radiation directly to tumors with remarkable precision. This combination aims to enhance the body's immune response against cancer, potentially leading to better outcomes than traditional chemotherapy or standard radiation treatments, which often affect both cancerous and healthy cells. By tailoring doses and targeting specific tumor sizes, these treatments could offer more personalized and effective cancer care.

What evidence suggests that combining pembrolizumab with SBRT could be effective for advanced cancer?

Research has shown that combining pembrolizumab with stereotactic body radiotherapy (SBRT) can enhance the immune system's ability to combat tumors. This combination has shown promise in treating various cancers, such as non-small cell lung cancer, by bolstering the body's natural defenses. For instance, one study found that pembrolizumab helped 18% of patients with soft tissue sarcoma, with their cancer not worsening for about 18 weeks on average. While the treatment effectively controlled cancer in specific areas, it did not outperform pembrolizumab alone overall. In this trial, participants will be enrolled in different cohorts to receive SBRT followed by pembrolizumab, as researchers investigate its effectiveness for certain patients and types of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Steven J. Chmura, M.D., Ph.D.

Principal Investigator

University of Chicago

Are You a Good Fit for This Trial?

Adults with advanced solid tumors not treatable by cure, who've tried all standard treatments. They must have good organ function, a life expectancy of at least 6 months, and agree to use contraception. Specific criteria include having certain blood cell counts and tumor sizes suitable for SBRT. Not eligible if on high-dose steroids, have active infections or autoimmune diseases, are pregnant/breastfeeding, or recently used investigational drugs.

Inclusion Criteria

Willing and able to provide written informed consent/assent for the trial.

Platelets ≥ 100,000 / mcL

Hemoglobin ≥ 8 g/dL

Exclusion Criteria

Hypersensitivity to pembrolizumab or any of its excipients.

I haven't had cancer treatment with a monoclonal antibody in the last 4 weeks or have recovered from its side effects.

I've had radiation therapy before in the area where SBRT is planned.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive stereotactic body radiotherapy (SBRT) over 1 week

1 week

Treatment

Participants receive pembrolizumab for up to 2 years or until disease progression or unacceptable side effects

Up to 24 months

Follow-up

Participants are monitored for progression-free survival and long-term side effects

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Stereotactic body radiotherapy (SBRT)

Trial Overview The trial is testing the safety of combining SBRT with pembrolizumab in patients with advanced solid tumors. It aims to find safe radiation doses for different organs when used alongside pembrolizumab and observe changes in the tumor post-SBRT.

How Is the Trial Designed?

Group I: Oligometastatic Cohort Experimental Treatment 2 Interventions

Patients with few tumors (4 or less) will be enrolled and their tumors treated with (stereotactic body radiotherapy) given over 1 week followed by treatment with pembrolizumab. Pembrolizumab dosing will continue for up to 2 years or until patients have disease progression or unacceptable side effects.

Group II: Large Volume Tumors Cohort Experimental Treatment 2 Interventions

Patients with large tumors will be enrolled and their tumors will be partially treated with (stereotactic body radiotherapy) given over 1 week followed by treatment with pembrolizumab. Pembrolizumab dosing will continue for up to 2 years or until patients have disease progression or unacceptable side effects.

Group III: Dose Escalation Cohort Experimental Treatment 2 Interventions

Patients will be enrolled to receive specific doses of radiation (stereotactic body radiotherapy) given over 1 week followed by treatment with pembrolizumab. Pembrolizumab dosing will continue for up to 2 years or until patients have disease progression or unacceptable side effects. Enrollment will continue until best safe dose of SBRT is determined for each organ type.

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 Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

In a study of 68 patients with advanced solid tumors, the combination of stereotactic body radiotherapy (SBRT) followed by pembrolizumab showed a high one-year treated metastasis control rate of 89.5%, indicating effective tumor response regardless of whether the tumors received complete or partial radiation coverage.

The study found that treated metastasis control (TMC) was significantly associated with improved overall survival, and SBRT altered tumor gene expression by increasing immune-related genes while decreasing those related to cell cycle and DNA repair, suggesting a mechanism for enhanced immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Luke, JJ., Onderdonk, BE., Bhave, SR., et al.[2021]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

The ESPERa trial is designed to evaluate the efficacy and safety of adding Stereotactic Body Radiotherapy (SBRT) to pembrolizumab-pemetrexed maintenance therapy in advanced non-small cell lung cancer (NSCLC) patients who have shown a response or stability after initial treatment, with the primary goal of improving progression-free survival (PFS).

Preliminary data suggest that combining immunotherapy with radiotherapy is safe and effective, but the systematic integration of these treatments in first-line therapy for NSCLC is still under investigation, highlighting the potential for SBRT to enhance treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study Design and Rationale for Espera Trial: A Multicentre, Randomized, Phase II Clinical Trial Evaluating the Potential Efficacy of Adding SBRT to Pembrolizumab-Pemetrexed Maintenance in Responsive or Stable Advanced Non-Squamous NSCLC After Chemo-Immunotherapy Induction. Belluomini, L., Dionisi, V., Palmerio, S., et al.[2022]

Pembrolizumab (Keytruda) has been approved for treating metastatic microsatellite instability-high colorectal cancer (CRC), showing promising efficacy in a small phase 2 clinical trial, which highlights the potential of immunotherapy in this cancer type.

Microsatellite instability-high CRCs that express PD-L1 are more likely to respond to PD-1/PD-L1 checkpoint inhibitors, while microsatellite-stable tumors show much less response, indicating the importance of PD-1/PD-L1 testing in guiding treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II-The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer. Marginean, EC., Melosky, B.[2022]

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]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

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]

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]

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