Combination Therapy for Non-Hodgkin's Lymphoma

Recruiting in Palo Alto (17 mi)

+1 other location

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

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

Breakthrough Therapy

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment for patients with Non-Hodgkin Lymphoma who haven't responded to other treatments. It uses special immune cells, a cancer drug, and an immune booster to target and kill cancer cells.

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.

What data supports the effectiveness of the treatment for Non-Hodgkin's Lymphoma?

Research shows that CD19-targeting therapies, like CAR T-cell therapy, have transformed the treatment of B-cell lymphomas, including Non-Hodgkin's Lymphoma, by achieving high response rates and long-lasting remissions in patients who have not responded to other treatments. ^{1 2 3 4 5}

Is the combination therapy for Non-Hodgkin's Lymphoma generally safe in humans?

The combination therapy involving CD19-targeted CAR-T cells has shown some safety concerns, such as cytokine release syndrome (a condition where the immune system releases too many proteins into the blood too quickly) and neurotoxicity (damage to the nervous system), but these are manageable with proper medical care. In a study with a different CAR-T cell therapy, no severe neurotoxicity or high-grade cytokine release syndrome was observed, indicating a generally safe profile. However, one case of dose-limiting toxicity (persistent low blood cell counts) was noted. ^{5 6 7 8 9}

How is the CD19t-haNK treatment different from other treatments for non-Hodgkin's lymphoma?

CD19t-haNK is a novel treatment that combines targeted therapy with natural killer (NK) cells, which are a type of immune cell that can attack cancer cells. This approach is different from existing treatments like CAR T-cell therapy, which uses modified T-cells to target cancer, as it potentially offers a unique mechanism of action by harnessing the body's natural immune response. ^{5 10 11 12 13}

Research Team

Eligibility Criteria

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

I am 18 years old or older.

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

Trial Timeline

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

Treatment Details

Interventions

• CD19t-haNK suspension (CAR T-cell Therapy)
• Cyclophosphamide (Cytotoxic agent)
• Fludarabine (Cytotoxic agent)
• N803 (Cytokine)
• Rituximab (Monoclonal Antibodies)

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.

Participant Groups

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

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

Findings from Research

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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Strategies to improve outcomes of autologous hematopoietic cell transplant in lymphoma. [2022]

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

CAR-T Engager proteins optimize anti-CD19 CAR-T cell therapies for lymphoma. [2022]

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

The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL). [2022]

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

CAR T-cell therapy for B-cell lymphoma. [2022]

5. United States 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. [2020]

6. United States 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. [2023]

7. United States 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. [2020]

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

CAR-T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope. [2020]

9. United States 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. [2021]

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

Chimeric antigen receptor modified T cell therapy in B cell non-Hodgkin lymphomas. [2021]

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

Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. [2022]

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

Targeted therapies for non-Hodgkin lymphoma: rationally designed combinations. [2019]

13. United States 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. [2019]