Pembro + CAR T-Cell Therapy for Large B-Cell Lymphoma

Recruiting at 2 trial locations

Overseen By Megan f Forsyth

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jennifer Crombie, MD

Must not be taking: Investigational agents, Live vaccines

Disqualifiers: Pregnancy, HIV, Hepatitis B, 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: 3

Duration: Up to 2 years

35 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 individuals with primary mediastinal B-cell lymphoma, particularly those whose cancer has returned after previous treatments. It examines the effectiveness of pembrolizumab and CAR T-cell therapy (a type of immune therapy) in fighting cancer together. Participants will receive these treatments to determine if the combination can better control or reduce the cancer. This trial suits individuals who have undergone at least one prior treatment for this type of lymphoma and are not eligible for a stem cell transplant. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important 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 cannot participate if you are on certain investigational agents or have received specific treatments recently, like systemic anti-cancer therapy within 2 weeks or investigational agents within 4 weeks.

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 certain B-cell lymphomas, even after CAR T-cell therapy. Some studies found it effective for patients whose cancer returned after these treatments, though side effects can still occur.

CAR T-cell therapy has delivered promising results, particularly for patients with large B-cell lymphoma, and it can lead to long-lasting improvements. However, older and frailer patients might experience more infections during treatment.

The combination of pembrolizumab and CAR T-cell therapy remains under study. Researchers are closely monitoring the safety of this combination, but early results suggest it can be safe for many patients. Being aware of potential side effects is important. Always consult healthcare providers about the risks and benefits before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining CAR T-cell therapy with Pembrolizumab for treating large B-cell lymphoma because it offers a unique approach compared to standard chemotherapy and existing immunotherapies. CAR T-cell therapy involves engineering a patient's own T-cells to better recognize and attack cancer cells, providing a highly personalized and targeted treatment option. Pembrolizumab, an immune checkpoint inhibitor, complements this by blocking a pathway that tumors often use to hide from the immune system, potentially enhancing the effectiveness of the CAR T-cells. This combination could lead to more durable remissions and improved outcomes for patients who have not responded well to other treatments.

What evidence suggests that the combination of pembrolizumab and CAR T-cell therapy could be an effective treatment for primary mediastinal B-cell lymphoma?

In this trial, participants will receive a combination of pembrolizumab and CAR T-cell therapy. Research has shown that pembrolizumab effectively treats patients with relapsed or hard-to-treat primary mediastinal B-cell lymphoma, extending survival and maintaining a good safety profile. Additionally, CAR T-cell therapy, which targets specific proteins on cancer cells, has significantly improved outcomes in various difficult-to-treat B-cell lymphomas, resulting in longer remission periods. These treatments enhance the immune system's ability to fight cancer cells more effectively. Together, they offer promising options for patients whose lymphoma has returned after previous treatments. ^{2 6 7 8 9}

Who Is on the Research Team?

Jennifer Crombie, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults (≥18 years) with primary mediastinal B-cell lymphoma that's come back or didn't respond to at least two treatments, or relapsed within a year of initial treatment. They must have measurable cancer on scans and agree to use effective contraception. People can't join if they've had certain other cancers, severe allergies to trial drugs, active infections like hepatitis or HIV, recent heart issues, uncontrolled diseases that could affect the study, or are pregnant.

Inclusion Criteria

I have a lymphoma lesion that shows up on PET/CT scans.

I am fully active or can carry out light work.

My blood counts meet the required levels for treatment.

Exclusion Criteria

Patients in urgent need of cytoreductive therapy

Participants who are receiving any other investigational agents

I have been treated for an autoimmune disease in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Lymphodepletion

Participants undergo leukapheresis for CAR T-cell manufacturing and receive lymphodepleting chemotherapy (fludarabine, cyclophosphamide) prior to CAR T-cell therapy infusion

3 weeks

Inpatient stay for leukapheresis and chemotherapy

Treatment

Participants receive pembrolizumab and CAR T-cell therapy. Pembrolizumab is administered every 3 weeks for up to 2 years, unless there is confirmed progression of disease or unacceptable toxicity

Up to 2 years

Inpatient stay for CAR T-cell therapy, outpatient visits every 3 weeks for pembrolizumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• CAR T-cell Therapy
• Pembrolizumab

Trial Overview

The trial is testing pembrolizumab combined with CAR T-cell therapy (axicabtagene-ciloleucel or lisocabtagene maraleucel), plus chemotherapy drugs cyclophosphamide and fludarabine. It aims to see if this mix can help people whose B-cell lymphoma has returned after previous treatments.

How Is the Trial Designed?

Group I: PEMBROLIZUMAB Experimental Treatment 4 Interventions

* Participants will undergo (leukapheresis) for manufacturing of commercial product as per standard of care (SOC) Cycle 1 Day -21or earlier * Pembrolizumab will be administered per protocol on cycle 1 day -20 and on day +1 following Chimeric Antigen Receptor (CAR) Therapy Infusion infusion, every 3 weeks for up to 2 years, unless there is confirmed progression of disease or unacceptable toxicity. * Upon the completion of successful manufacturing, patients will undergo lymphodepleting chemotherapy (fludarabine, cyclophosphamide) for chimeric antigen receptor (CAR) therapy infusion as per SOC. * Participants will receive Chimeric Antigen Receptor (CAR) Therapy Infusion (SOC) on day 0 in the hospital and will remain in the inpatient setting for observation for a minimum of 7 days or until CAR T-cell toxicities resolve to grade 1 or better. The choice of CAR-T product will be left to the discretion of the treating investigator.

CAR T-cell Therapy is already approved in United States, European Union for the following indications:

Approved in United States as CAR T-cell Therapy for:

• Relapsed or refractory B-cell acute lymphoblastic leukemia
• Relapsed or refractory B-cell non-Hodgkin's lymphoma
• Relapsed or refractory mantle cell lymphoma
• Relapsed or refractory follicular lymphoma
• Relapsed or refractory multiple myeloma

Approved in European Union as CAR T-cell Therapy for:

• Relapsed or refractory B-cell acute lymphoblastic leukemia
• Relapsed or refractory B-cell non-Hodgkin's lymphoma
• Relapsed or refractory mantle cell lymphoma

Who Is Running the Clinical Trial?

Jennifer Crombie, MD

Lead Sponsor

Trials

2

Recruited

80+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

CD19-directed CAR T-cell therapy has significantly transformed the treatment approach for aggressive B-cell non-Hodgkin lymphoma, offering new hope for patients.

There are currently three commercially available CAR T-cell therapies targeting CD19, indicating a growing acceptance and application of this innovative immunotherapy in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cell Therapy for Relapsed/Refractory Aggressive Large B-Cell Lymphoma. Gideon, J.[2023]

In a study of 59 patients with relapsed/refractory extranodal natural killer/T-cell lymphoma treated with pembrolizumab, the overall response rate was 40.7%, with 28.8% achieving a complete response, indicating its potential efficacy as a salvage therapy.

While pembrolizumab showed modest effectiveness, it was associated with some grade 3 or 4 adverse events in 20.3% of patients, with neutropenia being the most common, suggesting that while it can be beneficial, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea. Lee, JY., Kwon, JH., Hur, JY., et al.[2023]

CAR T cell therapy, particularly targeting B cell maturation antigen (BCMA), has shown promising efficacy in early clinical trials for treating multiple myeloma, indicating its potential as a new treatment option.

Recent research has also demonstrated that CAR T cells targeting activated integrin β7 can effectively eliminate multiple myeloma cells, including specific B cell types, and preparations for a clinical trial are underway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy for multiple myeloma. Hasegawa, K., Hosen, N.[2020]

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 (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) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

In a study of seven patients with refractory natural killer/T-cell lymphoma (NKTCL), treatment with the anti-PD-1 antibody pembrolizumab resulted in a 57% overall response rate, with two patients achieving complete responses and two achieving partial responses after a median of four treatment cycles.

The treatment was generally well-tolerated, with manageable adverse events, although immune-related pneumonitis was a notable side effect, indicating that PD-1 blockade could be a promising option for patients who have not responded to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. Li, X., Cheng, Y., Zhang, M., et al.[2019]

In a study involving 12 patients with B-cell lymphomas who had relapsed or were refractory to CD19-directed CAR T-cell therapy, pembrolizumab was found to be well tolerated, with only a few cases of significant adverse effects, primarily neutropenia.

After treatment with pembrolizumab, 33% of patients showed clinical benefit, including one complete response and two partial responses, along with evidence of increased CAR T-cell activation and reduced exhaustion, suggesting that pembrolizumab may help enhance the effectiveness of CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy. Chong, EA., Alanio, C., Svoboda, J., et al.[2023]

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]

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 monoclonal antibody targeting PD-1, has shown significant clinical efficacy in treating Hodgkin Lymphoma and promising early results in certain subtypes of Non-Hodgkin Lymphoma, particularly those with genetic similarities to HL.

Current data suggest that pembrolizumab has a favorable safety profile and efficacy as a single agent in treating diffuse large B cell lymphomas, with future strategies likely to focus on biomarker-driven approaches and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of diffuse large B-cell lymphoma. Sheikh, S., Kuruvilla, J.[2020]

CAR-T cell therapy combined with anti-PD-1 immunotherapy shows promising efficacy in treating lymphoma, with an overall response rate of 65% based on an analysis of 57 patients from 5 clinical trials.

The most common adverse effect observed was fever, with a pooled incidence of 59%, indicating that while the therapy is effective, it does come with notable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients. Zhou, Y., Mu, W., Wang, C., et al.[2023]

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