Nemtabrutinib + Pembrolizumab for Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must be taking: Antiretrovirals, Hepatitis B antivirals

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Immunodeficiency, Active CNS metastases, 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: 42

Duration: 2 years

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of combining two drugs, nemtabrutinib and pembrolizumab, in treating Richter transformation, diffuse large B-cell lymphoma subtype (RT-DLBCL). Nemtabrutinib, a kinase inhibitor, targets cancer cells to halt their growth, while pembrolizumab, an immunotherapy, aids the immune system in attacking the cancer. The trial aims to determine if these treatments together are more effective at eliminating cancer cells. Suitable candidates have RT-DLBCL and have either not responded to previous treatments or cannot undergo standard chemotherapy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on anti-retroviral therapy for HIV or hepatitis B antiviral therapy, you must continue these throughout the study. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that nemtabrutinib and pembrolizumab are likely to be safe for humans?

Previous studies have shown that nemtabrutinib holds promise in treating blood cancers, but about 89% of patients experienced serious side effects. The most common was neutropenia, a drop in white blood cells that fight infections.

Pembrolizumab, by contrast, appears to have a safer profile. Some studies reported no serious side effects with potentially fatal outcomes. It has been used to treat other types of cancer and is generally well-received by patients.

This trial uses both drugs together. While pembrolizumab is usually well-tolerated, nemtabrutinib has caused significant side effects in past studies. Participants should consider this when deciding whether to join the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining nemtabrutinib with pembrolizumab for treating lymphoma because this duo offers a fresh approach compared to existing options. Nemtabrutinib is an innovative agent that targets Bruton’s tyrosine kinase (BTK), a key player in lymphoma cell survival, making it potentially more effective against certain lymphoma types. When paired with pembrolizumab, a well-known immune checkpoint inhibitor, the combination aims to enhance the immune system's ability to fight cancer more robustly. This partnership between a novel BTK inhibitor and an established immunotherapy could offer a powerful new line of defense against lymphoma, potentially improving patient outcomes.

What evidence suggests that nemtabrutinib and pembrolizumab might be an effective treatment for RT-DLBCL?

Research has shown that combining nemtabrutinib and pembrolizumab, the treatments studied in this trial, might help treat certain types of lymphoma, including Richter transformation diffuse large B-cell lymphoma (RT-DLBCL). Nemtabrutinib blocks a protein called BTK, often found in high amounts in these cancer cells, possibly stopping their growth. Pembrolizumab, an immunotherapy, helps the immune system find and attack cancer cells. In previous studies, pembrolizumab alone had a 58% success rate in treating lymphoma that returned or didn't respond to other treatments. When used together, these treatments showed a longer time before the disease worsened, averaging 7.6 months, compared to using pembrolizumab alone. These results suggest that the combination could be promising for patients with RT-DLBCL. ^{6 7 8 9 10}

Who Is on the Research Team?

Matthew J Cortese

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with a specific type of lymphoma known as Richter transformation, diffuse large B-cell subtype. It's designed to see if combining two drugs, nemtabrutinib and pembrolizumab, can effectively treat this cancer. Participants should have this particular diagnosis to join.

Inclusion Criteria

My platelet count is at least 25,000, even with transfusions.

My hemoglobin level is at least 7gm/dL, transfusions are okay.

Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria

I have active brain metastases or carcinomatous meningitis.

Unwilling or unable to follow protocol requirements

I have or had lung inflammation that needed steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive nemtabrutinib orally once daily and pembrolizumab intravenously every 21 days for up to 35 cycles

2 years

35 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

3 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Nemtabrutinib
• Pembrolizumab

Trial Overview

The study is testing the effectiveness of nemtabrutinib (a kinase inhibitor that targets abnormal proteins in certain white blood cells) combined with pembrolizumab (an immunotherapy drug). The goal is to determine if this combination helps control or reduce cancer growth in RT-DLBCL patients.

How Is the Trial Designed?

Group I: Treatment (nemtabrutinib, pembrolizumab) Experimental Treatment 9 Interventions

Patients receive nemtabrutinib PO QD on days 1-21 of each cycle and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening, PET/CT or CT and blood sample collection throughout the trial. Patients may also undergo bone marrow biopsy throughout the trial.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

Published Research Related to This Trial

Pembrolizumab, an anti-PD-1 therapy, shows a high objective response rate of 84.5% in patients with refractory or recurrent NK/T-cell lymphoma, indicating its efficacy as a treatment option.

The treatment resulted in a complete response rate of 61.6% and demonstrated good disease-free survival ranging from 2 to 48 months, with low adverse events reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of PD-1 blockade in refractory/relapsed natural killer T-cell lymphomas: a systematic review and synthesis of case reports. Rivera-Francia, VM., Failoc-Rojas, VE., Villacorta-Carranza, R., et al.[2023]

Nivolumab and pembrolizumab, both anti-PD-1 therapies, show promising efficacy in treating relapsed or refractory lymphoma, with an overall response rate of 58% and a 6-month overall survival rate of 96% across 10 studies involving 718 patients.

While both treatments have tolerable adverse effects, pembrolizumab is associated with fewer instances of fatigue and rash compared to nivolumab, and patients with Hodgkin lymphoma respond better to treatment than those with non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Anti-PD-1 Monoclonal Antibodies in Patients With Relapsed or Refractory Lymphoma: A Meta-Analysis of Prospective Clinic Trails. Zhou, H., Fu, X., Li, Q., et al.[2020]

Pembrolizumab, an immunotherapy for advanced non-small-cell lung cancer (NSCLC), significantly improves progression-free and overall survival compared to traditional chemotherapy, with fewer side effects, particularly in patients with high PD-L1 expression (≥50%).

In combination with pemetrexed and carboplatin, pembrolizumab also enhances treatment effectiveness and maintains manageable toxicity, leading to a shift in first-line treatment strategies for advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Reck, M.[2018]

Pembrolizumab, a monoclonal antibody that blocks PD-1, effectively enhances antitumor immune responses and has been approved for treating advanced melanoma, renal cell cancer, and non-small cell lung cancer.

In vivo studies using PET imaging showed that pembrolizumab is stable in circulation and primarily accumulates in the liver and spleen, providing valuable insights into its pharmacokinetics and potential for optimizing dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab. England, CG., Ehlerding, EB., Hernandez, R., et al.[2020]

In a phase 3 trial involving 305 patients with advanced non-small-cell lung cancer (NSCLC) expressing PD-L1, pembrolizumab significantly improved median progression-free survival to 10.3 months compared to 6.0 months with chemotherapy, indicating its efficacy as a treatment option.

Patients receiving pembrolizumab also experienced fewer treatment-related adverse events (73.4% vs. 90.0% for chemotherapy), highlighting its safety profile alongside its effectiveness in prolonging survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

Pembrolizumab, an immune checkpoint inhibitor used for treating non-small cell lung cancer, is generally well tolerated, but can lead to rare immune-mediated adverse effects such as pleuropericarditis, as seen in a case involving a 64-year-old female patient.

The patient was effectively treated with colchicine, furosemide, and methylprednisolone, leading to symptom improvement and a decision to discontinue pembrolizumab, after which she remained asymptomatic for six months, highlighting the importance of recognizing and managing potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An unusual case of checkpoint-inhibitor-induced pleuropericarditis. Suarez, ZK., Finke, AC., Hospedales, E., et al.[2023]

Pembrolizumab, when combined with carboplatin and pemetrexed, significantly improves overall and progression-free survival rates in patients with non-small cell lung cancer (NSCLC), demonstrating its efficacy as a treatment option.

This case report highlights a unique instance of immune-mediated sarcoidosis developing in a patient with NSCLC after receiving pembrolizumab, indicating potential immune-related side effects of this therapy that require further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. Fakhri, G., Akel, R., Salem, Z., et al.[2022]

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]

Pembrolizumab, an anti-PD-1 antibody, has been approved for treating unresectable or metastatic melanoma, especially in patients who have progressed after ipilimumab treatment, marking a significant advancement in immuno-oncology.

The drug has also received breakthrough status for treating non-small cell lung cancer (NSCLC) that is EGFR mutation-negative and ALK rearrangement-negative, indicating its broad potential in cancer therapy, with ongoing trials to explore its use in various tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab. Khoja, L., Butler, MO., Kang, SP., et al.[2022]

An elderly male patient on pembrolizumab developed four autoimmune toxicities, including type 1 diabetes and pneumonitis, highlighting the risk of multiple immune-related adverse events associated with this treatment.

The case suggests that aging may increase susceptibility to these adverse effects, necessitating close monitoring and prompt management, including stopping the immunotherapy and using steroids for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab. Kethireddy, N., Thomas, S., Bindal, P., et al.[2021]

In a study of 145 patients with PD-L1 strongly positive non-small-cell lung cancer (NSCLC), those with higher PD-L1 expression (≥ 75%) experienced better treatment outcomes with pembrolizumab, showing a higher objective response rate (51% vs. 33%) and longer progression-free survival (13.9 months vs. 5.2 months).

Patients with liver metastasis had significantly poorer responses to pembrolizumab, with an objective response rate of only 20% compared to 47% in those without liver metastasis, indicating that both PD-L1 expression and liver metastasis are important predictors of treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Efficacy of Pembrolizumab According to Metastatic Sites in Patients With PD-L1 Strongly Positive (TPS ≥ 50%) NSCLC. Takeyasu, Y., Yoshida, T., Shibaki, R., et al.[2021]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06863402

Nemtabrutinib and Pembrolizumab for the Treatment of ...

Giving nemtabrutinib in combination with pembrolizumab may kill more cancer cells in patients with RT-DLBCL. Detailed Description. PRIMARY OBJECTIVE: I. To ...

2.

withpower.com

withpower.com/trial/nemtabrutinib-pembrolizumab-for-lymphoma-1f820

Nemtabrutinib + Pembrolizumab for Lymphoma

Nivolumab and pembrolizumab, both anti-PD-1 therapies, show promising efficacy in treating relapsed or refractory lymphoma, with an overall response rate of 58% ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11720094/

Updates in the Management of Richter Transformation - PMC

The median PFS was 2.6 months (95% CI 1.6–3.6) with pembrolizumab compared to 7.6 months (95% CI 2.3–13.3) in the combination cohort. Twenty-one ...

4.

merck.com

merck.com/news/merck-data-at-the-ash-2024-annual-meeting-highlights-promising-hematology-pipeline-with-diverse-range-of-investigational-assets-and-novel-modalities/

Merck Data at the ASH 2024 Annual Meeting Highlights ...

Efficacy and safety of pembrolizumab every six weeks in relapsed/refractory classical Hodgkin lymphoma or primary mediastinal B-cell lymphoma: ...

5.

onclive.com

onclive.com/view/dr-jurczak-on-the-efficacy-and-safety-of-nemtabrutinib-in-r-r-follicular-lymphoma

Dr Jurczak on the Efficacy and Safety of Nemtabrutinib in ...

Wojciech Jurczak, MD, PhD, discusses the safety and efficacy of nemtabrutinib, a noncovalent reversible BTK inhibitor in relapsed or refractory follicular ...

6.

ashpublications.org

ashpublications.org/blood/article/144/Supplement%201/3016/533676/Nemtabrutinib-a-Noncovalent-Reversible-BTK

Nemtabrutinib, a Noncovalent Reversible BTK Inhibitor in ...

Nemtabrutinib demonstrated promising antitumor activity in a heavily refractory population of pts with marginal zone lymphoma post chemoimmunotherapy and ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10428690/

UPDATED ANALYSIS OF BELLWAVE-001: A PHASE ...

Nemtabrutinib 65 mg continued to show promising and durable antitumor activity in pts with R/R CLL/SLL and a manageable safety profile in pts with hematologic ...

8.

onclive.com

onclive.com/view/dr-jurczak-on-the-role-of-nemtabrutinib-in-r-r-follicular-lymphoma-management

Dr Jurczak on the Role of Nemtabrutinib in R/R Follicular ...

The median progression-free survival was 5.5 months (95% CI, 2.8-NR), with 34% of patients progression free at 6 months. Although the median ...

9.

sohoonline.org

sohoonline.org/SOHO/SOHO/News/First%20Data%20on%20Nemtabrutinib%20in%20Relapsed%20or%20Refractory%20Hematologic%20Malignancies.aspx

First Data on Nemtabrutinib in Relapsed or Refractory ...

Regarding safety, 37 (89%) patients experienced grade 3 or higher treatment-emergent adverse events. The most common events were neutropenia in ...

10.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04728893

NCT04728893 | Efficacy and Safety of Nemtabrutinib (MK- ...

The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies.