Combination Therapy for Non-Hodgkin's Lymphoma

Recruiting at 2 trial locations

Overseen By Mark Nelson

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: ImmunityBio, Inc.

Must not be taking: Systemic corticosteroids, Anti-CD19, Anti-CD20, others

Disqualifiers: Autoimmune disease, CNS disease, organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination therapy for individuals with Non-Hodgkin's Lymphoma, a cancer affecting the lymphatic system. Researchers are testing CD19 t-haNK suspension (a type of cell therapy) both alone and with other drugs, including rituximab and an IL-15 superagonist, to determine if they work better together. The trial is open to those who have undergone at least two unsuccessful chemotherapy treatments and have CD19- and CD20-positive B-cell lymphoma. Participants should have active disease and have previously received treatments like rituximab. 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 new therapy.

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, you cannot participate if you are taking medications that have an adverse reaction with the study drugs.

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

Research has shown that CD19 t-haNK therapy was well-tolerated in earlier studies. For instance, patients with Waldenstrom macroglobulinemia, a type of non-Hodgkin's lymphoma, fully responded to the treatment. These patients had already tried many other treatments, highlighting the therapy's potential even in difficult cases.

When combined with rituximab, CD19 t-haNK underwent safety checks, with careful monitoring of vital signs and other health indicators to ensure participants' well-being. This combination aims to enhance treatment effectiveness while maintaining safety.

Researchers are also studying the addition of N-803 to CD19 t-haNK and rituximab. The goal is to determine if these three can work together safely and effectively. In these early stages, close monitoring helps quickly identify any side effects.

In summary, initial findings suggest the treatments are generally well-tolerated, but more research is needed to confirm safety in a larger group of patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CD19 t-haNK for Non-Hodgkin's Lymphoma because it uses a novel approach by combining engineered natural killer (NK) cells with targeted antibodies. Unlike standard treatments like chemotherapy and rituximab alone, CD19 t-haNK targets cancer cells with enhanced precision by using NK cells that are engineered to specifically recognize and attack the CD19 marker on lymphoma cells. Additionally, in one arm of the trial, the combination with N-803, an immune-stimulating agent, is expected to boost the immune response even further. This innovative mechanism aims to improve treatment outcomes by enhancing the body's natural ability to fight cancer cells more effectively.

What evidence suggests that this trial's treatments could be effective for Non-Hodgkin's Lymphoma?

This trial will evaluate the effectiveness of different combination therapies for Non-Hodgkin's Lymphoma. Studies have shown that CD19 t-haNK therapy can lead to complete responses in some patients. Specifically, early findings revealed that the first two patients treated with CD19 t-haNK had no detectable cancer after treatment. In this trial, participants in Arm A will receive CD19 t-haNK combined with Rituximab, a combination that research suggests can be effective, often leading to long-lasting remissions. Participants in Arm B will receive CD19 t-haNK combined with both Rituximab and N-803, which may further enhance the immune system's response, potentially leading to better results. While more research is needed, these treatments have shown promise in effectively targeting cancer cells and have produced encouraging outcomes in some cases. ^{2 3 5 6 7}

Are You a Good Fit for This Trial?

Adults with certain types of B-cell Non-Hodgkin Lymphoma that have worsened after at least two chemotherapy treatments. Participants must have previously received anti-CD20 antibody therapy, be able to get a central line for drug infusions, and commit to follow-up visits. They should not be pregnant or breastfeeding and agree to use effective contraception.

Inclusion Criteria

Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines

Histologically documented CD19- and CD20-positive B-cell NHL with specific criteria including active disease after ≥ 2 lines of cytotoxic chemotherapy, received rituximab or another anti-CD20 antibody, failed autologous transplant or ineligible for autologous transplant, measurable disease by Lugano classification, CD19- and CD20-positive disease on most recent biopsy, history of CNS involvement with no evidence of CNS involvement by cytology and flow cytometry, ECOG performance status of 0 to 1, expected survival > 12 weeks, willing and able to have central line placed for study drug infusions, stated willingness to comply with study procedures, able to attend required study visits and return for adequate follow-up, agreement to practice effective contraception for female subjects of child-bearing potential and nonsterile males

Exclusion Criteria

History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon

Known hypersensitivity to any component of the study medication(s), including anaphylactic reaction to sulfur-containing medications

Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Subjects receive lymphodepleting chemotherapy followed by a single 4-week cycle of the CD19 t-haNK single-agent regimen

4 weeks

Weekly visits for monitoring

Combination Treatment

Subjects receive lymphodepleting chemotherapy followed by a single 4-week cycle of CD19 t-haNK in combination with rituximab (cohort A) or in combination with rituximab and N-803 (cohort B)

4 weeks

Weekly visits for monitoring

Extended Treatment

Up to 4 repeated 4-week cycles of CD19 t-haNK in combination with rituximab (cohort A) or in combination with rituximab and N-803 (cohort B) without lymphodepleting chemotherapy

16 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• CD19t-haNK suspension
• Cyclophosphamide
• Fludarabine
• N803
• Rituximab

Trial Overview The trial is testing CD19t-haNK alone and combined with N803 (an IL-15 superagonist) and Rituximab in patients with relapsed/refractory B-cell Non-Hodgkin Lymphoma. It's an open-label, Phase 1 study where participants are randomly assigned to one of two groups.

How Is the Trial Designed?

Group I: Arm B Experimental Treatment 5 Interventions

Subjects in both cohorts will initially receive lymphodepleting chemotherapy followed by a single 4-week cycle of the CD19 t-haNK single-agent regimen. Following a 1-week rest period, subjects will then receive lymphodepleting chemotherapy followed by a single 4-week cycle of CD19 t-haNK in combination with rituximab (cohort A) or in combination with rituximab and N-803 (cohort B).

Group II: Arm A Experimental Treatment 4 Interventions

Subjects in both cohorts will initially receive lymphodepleting chemotherapy followed by a single 4-week cycle of the CD19 t-haNK single-agent regimen. Following a 1-week rest period, subjects will then receive lymphodepleting chemotherapy followed by a single 4-week cycle of CD19 t-haNK in combination with rituximab

CD19t-haNK suspension is already approved in United States for the following indications:

Approved in United States as CD19 t-haNK for:

• Non-Hodgkin's lymphoma refractory
• Recurrent Non-Hodgkin Lymphoma
• CD19 positive B-Cell Lymphoma
• CD20 positive B-Cell Lymphoma

Who Is Running the Clinical Trial?

ImmunityBio, Inc.

Lead Sponsor

Trials

75

Recruited

5,000+

Richard Adcock

ImmunityBio, Inc.

Chief Executive Officer since 2024

Information not available

Dr. Patrick Soon-Shiong

ImmunityBio, Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HDT-AHCT) is an effective treatment for lymphoma, with traditional regimens like BEAM and CBV being commonly used.

Exploring alternative conditioning regimens and incorporating maintenance therapy after transplantation may enhance patient outcomes by reducing toxicity while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies to improve outcomes of autologous hematopoietic cell transplant in lymphoma. Dahi, PB., Lazarus, HM., Sauter, CS., et al.[2022]

In a study involving 9 patients with relapsed or refractory B cell non-Hodgkin's lymphoma, both CD28 and 4-1BB targeted CAR-T cells showed similar antitumor efficacy, achieving a complete response rate of 67% within 3 months.

However, the 4-1BB (BBz CAR-T) cells were better tolerated, with only mild adverse events, while the CD28 (28z CAR-T) cells caused severe side effects, leading to the discontinuation of further evaluation for that group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parallel Comparison of 4-1BB or CD28 Co-stimulated CD19-Targeted CAR-T Cells for B Cell Non-Hodgkin's Lymphoma. Ying, Z., He, T., Wang, X., et al.[2020]

Chimeric antigen receptor (CAR)-T cell therapy, specifically targeting CD19, has shown promising results in treating non-Hodgkin lymphomas (NHLs) resistant to standard therapies, leading to FDA and EMA approvals for tisagenlecleucel and axicabtagene ciloleucel.

While CAR-T cell therapy can cause significant adverse events like cytokine release syndrome and neurological toxicity, these effects are manageable with proper medical support, highlighting the importance of trained teams in administering this novel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. Hopfinger, G., Jäger, U., Worel, N.[2020]

In a study of 75 patients with large B-cell lymphoma receiving CAR T-cell therapy, high pretreatment levels of the cytokine IL6 were linked to severe immune-mediated toxicities like cytokine release syndrome (CRS) and neurotoxicity (NT).

The research also found that certain gene expressions in tumor biopsies indicated a proinflammatory tumor microenvironment, which may increase the risk of toxicity, suggesting that personalized management strategies could help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel. Faramand, R., Jain, M., Staedtke, V., et al.[2021]

In a phase 3 trial with 322 patients suffering from aggressive B-cell non-Hodgkin's lymphoma, tisagenlecleucel did not show superior efficacy compared to standard salvage chemotherapy and autologous stem-cell transplantation, with both groups having a median event-free survival of 3.0 months.

Response rates were similar between the two groups, with 46.3% of patients receiving tisagenlecleucel responding compared to 42.5% in the standard-care group, indicating that while tisagenlecleucel is a treatment option, it may not provide additional benefits over existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. Bishop, MR., Dickinson, M., Purtill, D., et al.[2022]

In a phase I clinical trial involving 10 patients with relapsed/refractory non-Hodgkin lymphoma, the engineered T cells expressing a bispecific CAR targeting CD19 and CD20 demonstrated a high overall response rate of 90%, with 70% achieving complete remission.

The treatment was found to be safe, with no cases of neurotoxicity and only one instance of dose-limiting toxicity, indicating that CART19/20 T cells can provide effective therapy with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma. Larson, SM., Walthers, CM., Ji, B., et al.[2023]

Recent advances in targeted therapies for non-Hodgkin lymphoma, particularly the anti-CD20 monoclonal antibody rituximab, are expected to significantly improve patient care by inhibiting specific disease pathways.

Combining rituximab with other agents, such as monoclonal antibodies, immunomodulatory drugs, and Bcl-2 inhibitors, shows promise for enhancing treatment efficacy, especially in patients who do not respond to rituximab alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies for non-Hodgkin lymphoma: rationally designed combinations. Martin, P., Leonard, JP.[2019]

Natural killer (NK) cells play a crucial role in the treatment of B cell non-Hodgkin lymphoma (NHL) through mechanisms like antibody-dependent cellular cytotoxicity (ADCC), particularly in the context of rituximab therapy.

Recent advancements in CAR T cell therapies have highlighted the potential of NK cell-directed treatments, which are expected to be integrated into standard NHL therapies due to their high safety profiles and effectiveness against lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL). Chu, Y., Lamb, M., Cairo, MS., et al.[2022]

CAR T-cell therapy targeting CD19 has transformed the treatment landscape for relapsed or refractory B-cell lymphomas, leading to rapid FDA approval for multiple lymphoma subtypes due to high response rates and durability.

Three second-generation anti-CD19 CAR T-cell products have been approved for use in aggressive non-Hodgkin's lymphoma, and ongoing research is focused on understanding treatment failures and improving outcomes for patients who do not respond to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphoma. Denlinger, N., Bond, D., Jaglowski, S.[2022]

Axicabtagene ciloleucel and tisagenlecleucel are FDA-approved CAR T cell therapies specifically designed to target CD19 in patients with relapsed or refractory aggressive B cell non-Hodgkin lymphoma, marking a significant advancement in cellular immunotherapy.

Despite their transformative potential, there are ongoing concerns about the appropriate use and potential short- and long-term toxicities of these therapies, prompting expert consensus to guide clinicians in their application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Jain, T., Bar, M., Kansagra, AJ., et al.[2020]

CAR-T cell therapy targeting the CD19 antigen has significantly changed treatment for patients with relapsed or refractory B cell non-Hodgkin lymphoma, with two FDA-approved products available: axicabtagene ciloleucel and tisagenlecleucel.

The review highlights the clinical outcomes and toxicity profiles of these CAR-T therapies, indicating their effectiveness across major B cell NHL subtypes, while also discussing new CAR-T constructs currently being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. Levin, A., Shah, NN.[2021]

In a study of 38 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), a treatment regimen combining paclitaxel with other drugs resulted in a total response rate of 46%, with 26% achieving a complete response and 20% a partial response.

The regimen demonstrated a manageable safety profile, with major toxicity primarily being hematologic, and only 10% of treatment cycles leading to severe infections, indicating that it is both effective and safe for patients who have not responded to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of paclitaxel in combination with mitoxantrone and ifosfamide/mesna for patients with relapsed or refractory non-Hodgkin's lymphoma after failure to cytarabine/cisplatin combination. Romaguera, JE., Rodriguez, MA., Hagemeister, FB., et al.[2019]

A novel CAR T Engager therapy was developed to prevent relapses in B cell lymphoma by binding to CD20 and displaying the CD19 extracellular domain, effectively increasing CD19 antigen density on lymphoma cells.

This innovative approach has shown promising results in both laboratory tests and animal models, successfully preventing and reversing lymphoma relapse, even in cases where CD19 expression is lost or reduced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Engager proteins optimize anti-CD19 CAR-T cell therapies for lymphoma. Su, L., Wu, L., Lobb, RR., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05618925

NCT05618925 | Study for Subjects With Relapsed/ ... This is a phase 1, first-in-human (FIH), open-label study to evaluate the safety of CD19 t-haNK as a single agent and the safety and preliminary efficacy of ...

2. immunitybio.com immunitybio.com/immunitybio-reports-complete-responses-in-non-hodgkin-waldenstrom-lymphoma-patients-with-chemotherapy-free-first-in-class-cd19-car-nk-immunotherapy/

CD19 CAR-NK is a targeted high- ... Single-agent CD19 CAR-NK cell therapy achieved a complete response in third-line Waldenstrom macroglobulinemia (WM), a type of non-Hodgkin ...

3. onclive.com onclive.com/view/cd19-t-hank-leads-to-complete-responses-in-waldenstrom-macroglobulinemia

CD19 t-haNK Leads to Complete Responses in ... CD19 t-haNK therapy showed complete responses in heavily pretreated Waldenstrom macroglobulinemia patients, with sustained remissions for six ...

4. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/471179

Study for Subjects with Relapsed/Refractory Non-Hodgkin ... Experimental: CD19 t-haNK with Rituximab. Participants will initially receive a single 3-week cycle of the CD19 thaNK as a single-agent regimen.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT07125872

Open Label, Phase 2 Study of CD19t-haNK and N-803 in ... Open Label, Phase 2 Study of CD19t-haNK and N-803 in Combination With Rituximab in Participants With Relapsed/​ Refractory B-cell Non- Hodgkin Lymphoma.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06334991

NCT06334991 | Study for Subjects with Relapsed ... Overall safety evaluation in combining CD19 t haNK as a single agent with rituximab, Safety will be assessed for all participants and will include vital ...

7. immunitybio.com immunitybio.com/non-hodgkin-lymphoma/

Non-Hodgkin Lymphoma These CD-19-targeted NK (CD-19 t-haNK) cells will be tested in combination with our NK (and T-)-cell activator, N-803. The third component of the combination is ...