Pembrolizumab + Radiation Therapy for Non-Hodgkin's Lymphoma

Overseen By Chelsea C. Pinnix, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Autoimmune disease, Active infection, HIV, 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

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: 2

Duration: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining pembrolizumab, a type of immunotherapy, with radiation therapy effectively treats non-Hodgkin's lymphoma that has recurred or is unresponsive to current treatments. Pembrolizumab enhances the immune system's ability to attack cancer, and the study will assess whether adding radiation improves its efficacy. Suitable participants have aggressive forms of non-Hodgkin lymphoma that can be targeted by radiation and are willing to provide a tumor sample for research. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer 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 or any other form of immunosuppressive therapy, you must stop at least 7 days before starting the trial treatment.

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

Research has shown that pembrolizumab is usually well-tolerated by patients with non-Hodgkin lymphoma. In previous studies, some patients experienced blood-related side effects, but these were the most common and generally manageable. Pembrolizumab has produced positive results in similar patient groups.

External beam radiation therapy is also considered safe for treating non-Hodgkin lymphoma. Past studies found that most side effects were mild to moderate, with only a small number of patients experiencing more serious reactions.

Both treatments have a history of safety, but like any treatment, they carry potential risks. Discussing these with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Pembrolizumab combined with radiation therapy is unique because it utilizes an immune checkpoint inhibitor to enhance the body's immune response against non-Hodgkin's lymphoma. While traditional treatments often involve chemotherapy or standalone radiation, pembrolizumab specifically targets the PD-1 pathway, a mechanism that tumors use to evade immune detection. Researchers are excited because this approach may boost the effectiveness of radiation therapy by making cancer cells more recognizable to the immune system, potentially leading to better outcomes with fewer side effects.

What evidence suggests that pembrolizumab and radiation therapy might be an effective treatment for non-Hodgkin's lymphoma?

Research has shown that pembrolizumab can help treat non-Hodgkin's lymphoma. One study found that 22% of patients responded positively, with some experiencing complete remission. External beam radiation therapy (EBRT) has also shown promising results, with about 90% of patients responding well. In this trial, participants will receive a combination of pembrolizumab and EBRT, which might enhance the treatment's effectiveness. This combination uses both the immune system and radiation to target the cancer, potentially stopping the tumor from growing or spreading. ^{1 2 4 6 7}

Who Is on the Research Team?

Chelsea C. Pinnix

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with relapsed or refractory non-Hodgkin lymphoma who can undergo radiation therapy, have measurable disease, and are in good health otherwise. They must not be pregnant, agree to use contraception, and cannot have had certain recent treatments or active infections like TB or hepatitis.

Inclusion Criteria

I am willing to use birth control during the study.

My lymphoma is confirmed to be an aggressive type.

Have measurable disease (>= 1.5 cm in the longest diameter for nodal or extranodal disease)

Exclusion Criteria

Has known psychiatric or substance abuse disorders

I have had a stem cell transplant from a donor.

I have been diagnosed with a specific autoimmune disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Patients undergo fractionated external beam radiotherapy (EBRT) daily for 5 consecutive days a week for up to 12 or 22 treatments

2.5 to 4.5 weeks

Daily visits for radiation treatment

Treatment

Patients receive pembrolizumab intravenously over 1 hour on day 2, repeating every 21 days for up to 35 cycles

Up to 24 months

1 visit every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

1 visit at 30 days, then every 3 months for 1 year, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• External Beam Radiation Therapy
• Pembrolizumab

Trial Overview The study is testing the combination of pembrolizumab (an immunotherapy drug) with external beam radiation therapy to see if it's more effective than pembrolizumab alone for treating non-Hodgkin lymphoma that has returned after treatment or hasn't responded to previous therapies.

How Is the Trial Designed?

Group I: Treatment (EBRT, pembrolizumab) Experimental Treatment 2 Interventions

Beginning on day 1, patients undergo fractionated EBRT daily for 5 consecutive days a week for up to 12 or 22 treatments. Patients also receive pembrolizumab IV over 1 hour on day 2. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 98 patients with advanced non-small-cell lung cancer (NSCLC), those who had previously received radiotherapy experienced significantly longer progression-free survival (4.4 months) and overall survival (10.7 months) when treated with pembrolizumab compared to those without prior radiotherapy.

The safety profile was acceptable, with similar rates of severe pulmonary toxicity between patients who had and had not received thoracic radiotherapy, suggesting that combining radiotherapy with pembrolizumab may be a beneficial treatment strategy for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Shaverdian, N., Lisberg, AE., Bornazyan, K., et al.[2022]

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]

In a study involving 9 patients with resectable stage IIIA non-small cell lung cancer (NSCLC), the addition of pembrolizumab to neoadjuvant chemotherapy and radiotherapy resulted in a promising 67% overall response rate, with 4 patients achieving a pathologic complete response.

However, the trial faced significant safety concerns, with serious adverse events occurring in 7 patients, including 2 fatal events, leading to the study's closure due to higher-than-expected toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Study of Concurrent Neoadjuvant Pembrolizumab Plus Chemoradiation Followed by Consolidation Pembrolizumab in Patients With Resectable Stage IIIA NSCLC. Lemmon, CA., Videtic, GMM., Murthy, S., et al.[2022]

In a study involving 8 patients with hormone receptor-positive metastatic breast cancer, combining pembrolizumab with palliative radiation therapy did not result in any objective responses, leading to the study's closure.

The median progression-free survival was only 1.4 months and overall survival was 2.9 months, indicating limited efficacy of this treatment combination in heavily pre-treated patients, although the treatment was generally safe with only one significant adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Barroso-Sousa, R., Krop, IE., Trippa, L., et al.[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]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., et al.[2022]

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]

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, 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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16770786/

Safety and efficacy of external beam radiation therapy for ... The overall response rate was 90% (26/29) with 12 complete responses (41%), 7 complete clinical responses (24%), 7 partial responses (24%), and 3 stable (10%).

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301610033535

Outcomes of Patients With Non-Hodgkin's Lymphoma ... Of all patients, 79% had a partial or complete response; 4 of the 8 responders in the EBRT + Bexxar group achieved a durable response of over 2 years, including ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00271050

NCT00271050 | External Beam Radiotherapy and Zevalin ... The purpose of the research study is to learn whether external beam radiation can be used as a safe and effective treatment for patients with bulky (≥ 5cm) ...

4. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.21998

Safety and efficacy of external beam radiation therapy for non ... This study demonstrates that EBRT can produce a very high ORR of 90% with 41% CR in tumor sites previously treated with RIT.

5. redjournal.org redjournal.org/article/S0360-3016(10)03353-5/abstract

Outcomes of Patients With Non-Hodgkin's Lymphoma ... Of all patients, 79% had a partial or complete response; 4 of the 8 responders in the EBRT + Bexxar group achieved a durable response of over 2 years, including ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8436835/

Radiotherapy for non-Hodgkin lymphomas: 2020 State of the ... Radiation therapy improves treatment outcome in patients with diffuse large B-cell lymphoma. Leukemia & Lymphoma 2011;52(10):1867–72. [DOI] ...

7. cancer.org cancer.org/cancer/types/non-hodgkin-lymphoma/treating/radiation-therapy.html

Radiation Therapy for Non-Hodgkin Lymphoma External beam radiation treatment for NHL might include beams made of photons (most common), protons, or electrons depending on the situation.