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

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Jennifer Crombie, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Jennifer Crombie, MD

Must not be taking: Investigational agents, Live vaccines

Disqualifiers: Pregnancy, HIV, Hepatitis B, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This research study is evaluating the combination of drugs, pembrolizumab with chimeric antigen receptor (CAR) T-cell therapy, as a possible treatment for primary mediastinal B-cell lymphoma that has recurred after prior treatment. The names of the study drugs involved in this study are: - Pembrolizumab Standard treatment will include: * CAR T-cell therapy (either axicabtagene-ciloleucel or lisocabtagene maraleucel) * Cyclophosphamide * Fludarabine

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.

What data supports the effectiveness of the treatment Pembro + CAR T-Cell Therapy for Large B-Cell Lymphoma?

Research shows that pembrolizumab, when used after CAR T-cell therapy, can help some patients with B-cell lymphomas who did not respond to or relapsed after initial CAR T-cell treatment. This combination may enhance the effectiveness of CAR T-cells by reducing their exhaustion and improving their ability to fight cancer. ^{1 2 3 4 5}

What safety data exists for Pembrolizumab (Keytruda) in humans?

Pembrolizumab (Keytruda) has been associated with some immune-related side effects, such as type 1 diabetes in 0.2% of cases and pneumonitis (lung inflammation) in 1%-5% of patients. Common side effects include fatigue, cough, nausea, and rash, while more serious immune-related reactions can affect organs like the liver and thyroid. ^{6 7 8 9 10}

How is the Pembro + CAR T-Cell Therapy treatment different for large B-cell lymphoma?

This treatment combines CAR T-cell therapy, which uses modified immune cells to target cancer cells, with pembrolizumab, a drug that helps reactivate exhausted immune cells. This combination aims to enhance the effectiveness of CAR T-cell therapy, especially in patients who have not responded to or have relapsed after initial CAR T-cell treatment. ^{1 2 5 11 12}

Research Team

Jennifer Crombie, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• CAR T-cell Therapy (CAR T-cell Therapy)
• Pembrolizumab (PD-1 Inhibitor)

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.

Participant Groups

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.

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

Findings from Research

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]

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]

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]

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]

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, 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]

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 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]

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]

References

1. Korea (South) pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea. [2023]

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

Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of diffuse large B-cell lymphoma. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients. [2023]

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

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

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

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

8. United States 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. [2021]

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

10. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy for multiple myeloma. [2020]