AZD0486 for Non-Hodgkin's Lymphoma

Recruiting in Palo Alto (17 mi)

+30 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Teneobio, Inc.

Disqualifiers: Other malignancy, Active CNS involvement, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment for patients with a type of lymphoma that hasn't responded to other treatments. The treatment works by connecting immune cells to cancer cells, helping the immune system destroy the cancer. This approach is innovative and promising in the treatment of malignant lymphoma.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment AZD0486 for Non-Hodgkin's Lymphoma?

Research shows that TNB-486, a part of the treatment, effectively kills tumor cells in models of B-cell non-Hodgkin's lymphoma with minimal side effects compared to other treatments. It works by engaging T-cells to attack cancer cells, showing promise as a new therapy for this type of lymphoma. ^{1 2 3 4 5}

Is AZD0486 (also known as TNB-486) generally safe for humans?

In preclinical studies, TNB-486 showed minimal cytokine release, which suggests lower risk of severe side effects compared to similar treatments. In a small study with a similar bispecific antibody, patients experienced mild side effects like fever and chills, indicating limited toxicity. ^{1 6 7 8 9}

How is the drug AZD0486 (TNB-486) different from other treatments for non-Hodgkin's lymphoma?

AZD0486 (TNB-486) is unique because it is a bispecific antibody that targets both CD19 on B cells and CD3 on T cells, leading to effective tumor cell destruction with minimal cytokine release, which reduces the risk of severe side effects compared to other treatments like CAR-T therapies. ^{1 3 4 10 11}

Research Team

David Sermer, MD

Principal Investigator

AstraZeneca

Eligibility Criteria

This trial is for adults with B-cell non-Hodgkin lymphoma that's come back or didn't respond after at least two treatments. They should be fairly active (ECOG ≤ 2), have good liver, bone marrow, and kidney function, and not be suitable for other effective therapies. Pregnant or breastfeeding women can't join.

Inclusion Criteria

My liver, bone marrow, and kidneys are functioning well.

I have a biopsy confirming I have follicular lymphoma.

I have had at least 2 treatments for my cancer but they didn't work or my cancer came back.

Exclusion Criteria

I had a severe reaction to previous T-cell therapy.

I have a history of serious heart problems.

I am not pregnant or breastfeeding.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

AZD0486 monotherapy administered intravenously on day 1 and 15 of 28-day cycles for up to 2 years

Up to 2 years

Bi-weekly visits (in-person) during cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Long-term follow-up

Monitoring of progression-free survival and other outcomes

48 months

Treatment Details

Interventions

• TNB-486 (CAR T-cell Therapy)

Trial Overview The study tests AZD0486 IV, a new type of drug aiming to engage immune T-cells against cancer cells in patients with specific types of relapsed or refractory B-cell lymphomas who've tried multiple previous therapies.

Participant Groups

Group I: AZD0486 Monotherapy Dose Escalation in Subjects with RR B-NHL Experimental Treatment 1 Intervention

AZD0486 monotherapy will be administered intravenously on day 1 and 15 of 28 day cycles for a maximum of 2 years or until discontinuation criteria are met. Depending on cohort, subjects may receive priming or step-up dosing during cycle 1 before reaching the target dose. While on study, subjects will be monitored for safety and efficacy with periodic disease assessment with PET/CT. If subject achieves two consecutive CRs after completing C6, then they may be eligible for monthly dosing

Who Is Running the Clinical Trial?

Teneobio, Inc.

Lead Sponsor

Trials

4

Recruited

490+

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

TeneoTwo Inc.

Lead Sponsor

Trials

1

Recruited

230+

Findings from Research

TNB-486, a fully human bispecific antibody targeting CD19 and CD3, shows promise in treating B cell non-Hodgkin lymphoma (B-NHL) by inducing tumor cell lysis with minimal cytokine release, addressing safety concerns associated with existing therapies like blinatumomab and CAR-T.

In preclinical models, TNB-486 effectively cleared CD19+ tumor cells in immunocompromised mice and demonstrated pharmacokinetics similar to conventional antibodies, suggesting it could be a safer and more effective option for patients with B-NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL. Malik-Chaudhry, HK., Prabhakar, K., Ugamraj, HS., et al.[2022]

The CD19/CD3 bi-specific antibody (BsAb) effectively targeted and bound to both CD19 and CD3-positive cells, demonstrating its potential for specific cancer therapy in non-Hodgkin's lymphoma (NHL).

In animal models, this BsAb not only stimulated T cell proliferation but also significantly inhibited tumor growth and prolonged survival in SCID mice, indicating its efficacy as a promising treatment option for NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fully human CD19/CD3 bi-specific antibody triggers potent and specific cytotoxicity by unstimulated T lymphocytes against non-Hodgkin's lymphoma. Zhou, Y., Gou, LT., Mu, B., et al.[2017]

The bispecific antibody CD20-TCB is designed to enhance T-cell engagement, which could improve the effectiveness of immunotherapy in treating B-cell lymphoma, particularly in patients with relapsed or refractory non-Hodgkin lymphoma.

Preclinical models have shown promising activity for CD20-TCB, suggesting it may offer a new therapeutic option for patients who have not responded to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunity War: A Novel Therapy for Lymphoma Using T-cell Bispecific Antibodies. Prakash, A., Diefenbach, CS.[2019]

The tetravalent tandem diabody (tanDb) targeting CD19 and CD3 effectively eliminated malignant B cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in 19 out of 23 cases, demonstrating its potential as a powerful immunotherapy.

Unlike other antibody formats, the tanDb induced strong T cell activation and proliferation in the presence of CD19+ target cells, allowing for effective tumor cell lysis at very low concentrations, making it a promising candidate for treating B-cell leukemias and lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of tetravalent bispecific CD19xCD3 recombinant antibody construct and CD28 costimulation on lysis of malignant B cells from patients with chronic lymphocytic leukemia by autologous T cells. Reusch, U., Le Gall, F., Hensel, M., et al.[2017]

The bispecific diabody (BsDb) targeting both CD19 and CD16 effectively recruits natural killer (NK) cells to attack non-Hodgkin's lymphoma cells, showing higher affinity for tumor cells compared to effector cells.

In a study with SCID mice, combining the CD19 x CD16 BsDb with another bispecific diabody and CD28 costimulation led to complete tumor elimination in 80% of cases, demonstrating a powerful synergistic effect in enhancing the anti-tumor response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic antitumor effect of bispecific CD19 x CD3 and CD19 x CD16 diabodies in a preclinical model of non-Hodgkin's lymphoma. Kipriyanov, SM., Cochlovius, B., Schäfer, HJ., et al.[2019]

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]

TNB-383B effectively induces the killing of plasma cells in bone marrow from patients with relapsed multiple myeloma, showing dose-dependent lysis starting at very low doses (0.001 μg).

The treatment leads to significant degranulation of cytotoxic T lymphocytes (CTLs) and modulates cytokine responses, with notable increases in IL-2/TNFα and IP10, indicating a robust immune response without significant T cell expansion or severe cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma. Foureau, DM., Bhutani, M., Robinson, M., et al.[2023]

The CD3 x CD19 bispecific antibody (BsAb) effectively induced the killing of malignant B cells by resting T cells in preclinical tests, but required repeated doses and IL-2 to achieve significant tumor cell reduction in a 14-day assay.

In a small clinical study involving 4 patients, BsAb showed limited toxicity, primarily causing grade II fever and chills, while improving T cell activation; however, no significant clinical effects were observed in a patient with chronic lymphocytic leukemia, suggesting that further testing in patients with lower tumor burdens may be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with CD3 x CD19 bispecific antibodies in patients with B cell malignancies. De Gast, GC., Van Houten, AA., Haagen, IA., et al.[2018]

Triple negative breast cancer (TNBC) shows a higher potential for responding to immunotherapy due to its characteristics, such as increased tumor infiltrating lymphocytes and higher PD-L1 expression, making it a promising target for innovative treatments.

Current research is focused on exploring new immunotherapeutic strategies beyond immune checkpoint inhibitors, as these could provide safer and more effective options for treating TNBC, which has a poor prognosis and resists conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy in triple negative breast cancer: beyond checkpoint inhibitors. Abdou, Y., Goudarzi, A., Yu, JX., et al.[2023]

Chimeric anti-CD20 monoclonal antibodies (MAbs) have shown promising results in treating B cell non-Hodgkin's lymphoma (NHL), leading to increased global use of these therapies over the past five years.

These anti-CD20 MAbs can be used effectively either alone or in combination with traditional chemotherapy, particularly in consolidating remission after high-dose chemotherapy and stem cell rescue, suggesting their growing importance in NHL treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD20-based therapy of B cell lymphoma: state of the art. Kosmas, C., Stamatopoulos, K., Stavroyianni, N., et al.[2013]

Rituximab has been approved as an effective treatment for relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL), marking a significant advancement in therapy options for this disease.

Ibritumomab (Zevalin), a radioimmunotherapy targeting the CD20 antigen, has shown promising overall response rates of 64% and 67% in completed Phase I/II trials for various NHL types, with further trials currently ongoing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioimmunotherapy of relapsed non-Hodgkin's lymphoma with zevalin, a 90Y-labeled anti-CD20 monoclonal antibody. Wiseman, GA., White, CA., Witzig, TE., et al.[2013]

References

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

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

A fully human CD19/CD3 bi-specific antibody triggers potent and specific cytotoxicity by unstimulated T lymphocytes against non-Hodgkin's lymphoma. [2017]

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

Immunity War: A Novel Therapy for Lymphoma Using T-cell Bispecific Antibodies. [2019]

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

Effect of tetravalent bispecific CD19xCD3 recombinant antibody construct and CD28 costimulation on lysis of malignant B cells from patients with chronic lymphocytic leukemia by autologous T cells. [2017]

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

Synergistic antitumor effect of bispecific CD19 x CD3 and CD19 x CD16 diabodies in a preclinical model of non-Hodgkin's lymphoma. [2019]

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

Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma. [2023]

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

Clinical experience with CD3 x CD19 bispecific antibodies in patients with B cell malignancies. [2018]

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

Immunotherapy in triple negative breast cancer: beyond checkpoint inhibitors. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Anti-CD20-based therapy of B cell lymphoma: state of the art. [2013]

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

Radioimmunotherapy of relapsed non-Hodgkin's lymphoma with zevalin, a 90Y-labeled anti-CD20 monoclonal antibody. [2013]