AZD5492 for B-Cell Lymphoma

(TITANium Trial)

Recruiting at 26 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Disqualifiers: CNS involvement, Burkitt's lymphoma, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

174 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase I/II study designed to evaluate if experimental T cell engaging antibody targeting CD20 AZD5492 is safe, tolerable and efficacious in participants with Relapsed or Refractory B-Cell Malignancies.

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

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 drug AZD5492 for B-Cell Lymphoma?

The drug zanubrutinib, a similar BTK inhibitor, has shown effectiveness in treating various B-cell lymphomas, including marginal zone lymphoma and follicular lymphoma, with high response rates and improved progression-free survival. This suggests that AZD5492, if similar, might also be effective for B-cell lymphoma. ^{1 2 3 4 5}

Is AZD5492 (zanubrutinib) safe for humans?

Zanubrutinib, also known as AZD5492, has been generally well tolerated in various studies for B-cell malignancies, with most side effects being mild to moderate. Some common side effects include bruising, infections, and diarrhea, while more serious side effects like neutropenia (low white blood cell count) and pneumonia were less common. Overall, it has shown a favorable safety profile in clinical trials. ^{1 5 6 7 8}

Eligibility Criteria

This trial is for individuals with B-Cell Malignancies that have not responded to or have returned after previous treatments. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be required to have a particular stage or type of disease.

Inclusion Criteria

I can do most of my daily activities on my own.

My condition worsened after two previous treatments.

My cancer is a type of B-cell lymphoma or leukemia.

Exclusion Criteria

I have side effects from cancer treatment that are moderate or worse, with some exceptions.

I haven't had a stem cell transplant or cell therapy in the last 3 to 6 months.

My lymphoma affects my brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD5492 monotherapy for Relapsed or Refractory B-Cell Malignancies

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Treatment Details

Interventions

• AZD5492

Trial Overview The study is testing AZD5492, an experimental T cell-engaging antibody targeting CD20. It's in early stages (Phase I/II) to see if it's safe, tolerable, and effective for treating Relapsed or Refractory B-Cell Malignancies.

Participant Groups

Group I: Module 1: AZD5492 Monotherapy Experimental Treatment 1 Intervention

AZD5492 monotherapy for Relapsed or Refractory B-Cell Malignancies.

Who Is Running the Clinical Trial?

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

Findings from Research

In the phase III ALPINE trial, zanubrutinib, a second-generation BTK inhibitor, demonstrated superior efficacy compared to ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Zanubrutinib not only showed a better safety profile but also significantly improved progression-free survival for patients, making it a promising treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK Inhibitor Options Expand for CLL/SLL. [2023]

Zanubrutinib has been approved for treating various lymphoproliferative disorders, providing a significant option for patients who have not responded to standard therapies.

A panel of experts identified unmet clinical needs in the use of zanubrutinib for specific lymphomas, such as Waldenström macroglobulinemia, and made recommendations for future studies to optimize its use, especially for less experienced healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmet clinical needs in the use of zanubrutinib in malignant lymphomas (Waldenström macroglobulinemia, marginal zone lymphoma and mantle cell lymphoma): A consensus-based position paper from an ad hoc expert panel. Zinzani, PL., Mauro, FR., Tedeschi, A., et al.[2023]

A clinical trial combining R-CHOP with the BTK inhibitor zanubrutinib (ZR-CHOP) showed a high complete response rate in newly diagnosed double-expressor diffuse large B-cell lymphoma (DEL), although some patients, including one with ATM and CD58 mutations, experienced disease progression.

In vitro drug sensitivity testing identified that the patient with mutations responded well to a combination of bortezomib, thalidomide, and dexamethasone (VTD), leading to a complete response after subsequent treatment with VTD plus gemcitabine, demonstrating the potential of personalized therapy based on drug sensitivity profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: Successful management of a refractory double-expressor diffuse large B-cell lymphoma patient under the guidance of in vitro high-throughput drug sensitivity test. Xing, L., Wang, H., Liu, D., et al.[2023]

In a study involving 18 patients with marginal zone lymphoma (MZL) treated with zanubrutinib, mutations in genes related to the NF-κB, NOTCH, and B-cell receptor pathways were found in 89% of the samples, indicating these mutations may play a significant role in the disease's response to treatment.

Specific mutations, such as MYD88 and TNFAIP3, were associated with improved progression-free survival (PFS), while KMT2D mutations were linked to worse PFS, highlighting the importance of genetic profiling in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma. Tatarczuch, M., Waltham, M., Shortt, J., et al.[2023]

In a study of 53 patients with relapsed/refractory marginal zone lymphoma (MZL) and follicular lymphoma (FL), the selective Bruton's tyrosine kinase inhibitor zanubrutinib showed an overall response rate of 80% for MZL and 36.4% for FL, indicating significant efficacy in these difficult-to-treat cancers.

Zanubrutinib was generally well tolerated, with most adverse events being mild (≤ grade 2), and no reports of atrial fibrillation/flutter, suggesting a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. Phillips, T., Chan, H., Tam, CS., et al.[2022]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, showed a high overall response rate of 94.5% in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma carrying the del(17p) mutation, indicating its efficacy in a challenging patient population.

The treatment was well tolerated, with an estimated 18-month progression-free survival rate of 88.6% and an overall survival rate of 95.1%, although some patients experienced adverse events, including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. Tam, CS., Robak, T., Ghia, P., et al.[2021]

In a phase 2 study involving 41 patients with relapsed or refractory non-GCB DLBCL, zanubrutinib showed a modest overall response rate of 29.3% and a complete response rate of 17.1%, indicating some effectiveness in this challenging subtype of lymphoma.

The safety profile of zanubrutinib was consistent with previous studies, with 48.8% of patients experiencing grade ≥ 3 adverse events, but no major hemorrhage or atrial fibrillation was reported, suggesting it may be a relatively safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma. Yang, H., Xiang, B., Song, Y., et al.[2022]

Zanubrutinib, a selective BTK inhibitor, was well-tolerated in a phase 1 study with 144 patients, showing no dose-limiting toxicities and achieving over 95% BTK occupancy in blood cells at all tested doses.

In patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), zanubrutinib demonstrated a remarkable overall response rate of 96.2% and a 100% estimated progression-free survival at 12 months, indicating strong efficacy with low major toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Tam, CS., Trotman, J., Opat, S., et al.[2021]

References

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

BTK Inhibitor Options Expand for CLL/SLL. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Unmet clinical needs in the use of zanubrutinib in malignant lymphomas (Waldenström macroglobulinemia, marginal zone lymphoma and mantle cell lymphoma): A consensus-based position paper from an ad hoc expert panel. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: Successful management of a refractory double-expressor diffuse large B-cell lymphoma patient under the guidance of in vitro high-throughput drug sensitivity test. [2023]

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

Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma. [2023]

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

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. [2022]

6. Italy pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]

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

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma. [2022]

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

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. [2021]