BGB-16673 for B-Cell Cancers

(CaDAnCe-101 Trial)

Recruiting at 146 trial locations

Overseen By Study Director, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: BeiGene

Must be taking: BTK inhibitors

Must not be taking: Corticosteroids

Disqualifiers: Prior malignancy, CNS involvement, 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

621 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new drug called BGB-16673 to find the best dose for patients. It aims to determine how well the drug works and its safety. The study involves finding the right dose and expanding testing to more patients.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that ongoing systemic corticosteroid treatment is an exclusion criterion, which might imply some restrictions. It's best to discuss your specific medications with the trial coordinators.

What data supports the effectiveness of the drug BGB-16673 for B-cell cancers?

Ibrutinib, a drug similar to BGB-16673, has shown positive results in treating B-cell cancers like chronic lymphocytic leukemia and diffuse large B-cell lymphoma by targeting specific pathways that help cancer cells survive and grow. This suggests that BGB-16673 might also be effective for B-cell cancers. ^{1 2 3 4 5}

What safety data exists for BGB-16673 (zanubrutinib) in humans?

Zanubrutinib, a Bruton's tyrosine kinase inhibitor, has been studied for safety in patients with B-cell cancers. Common side effects include a decrease in neutrophil count (a type of white blood cell), with some patients experiencing more severe cases. Overall, zanubrutinib was well tolerated, with most side effects being mild to moderate. ^{6 7 8 9 10}

How is the drug BGB-16673 different from other treatments for B-cell cancers?

BGB-16673 is unique because it may target specific pathways in B-cell cancers, similar to how ibrutinib targets Bruton's tyrosine kinase, which is crucial for B-cell survival and growth. This approach is different from traditional chemotherapy, as it focuses on disrupting cancer cell signaling rather than directly killing cells. ^{4 5 11 12 13}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for people with certain B-cell malignancies, including various types of lymphoma and leukemia. Participants must have measurable disease, may have had previous treatments (specific conditions apply), and should be in a relatively stable condition as indicated by an ECOG score of 0 to 2. Those who've had other cancers within the last two years or require ongoing treatment for another cancer are not eligible.

Inclusion Criteria

I was treated with a BTK inhibitor for at least 8 weeks, unless I couldn't tolerate it.

I can take care of myself and am up and about more than half of my waking hours.

I may or may not have had BTKi therapy, depending on my diagnosis and where I live.

Exclusion Criteria

I have a specific type of blood cancer or lymphoma.

I am currently on long-term steroid medication.

My B-cell cancer has affected or previously affected my brain or spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Monotherapy Dose Escalation

Dose escalation in specific subtypes of non-Hodgkin lymphoma to evaluate the safety and tolerability of BGB-16673.

Approximately 28 days

Phase 1: Monotherapy Safety Expansion

Participants with various B-cell malignancies will be enrolled at selected doses to help determine the recommended dose(s) for expansion.

Up to 47 weeks

Phase 2: Monotherapy Expansion

Cohorts of participants will be enrolled to receive the recommended dose(s) identified in Phase 1 to further evaluate the safety and efficacy of BGB-16673.

Approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

Treatment Details

Interventions

• BGB-16673

Trial Overview The study tests BGB-16673's optimal dosing levels in two parts: first, finding the right dose through monotherapy escalation; second, expanding safety studies at selected doses. It aims to determine how well this drug can treat different B-cell malignancies when given alone.

Participant Groups

Group I: Phase 2 (Monotherapy Expansion) Experimental Treatment 1 Intervention

Cohorts of participants with R/R CLL/SLL, R/R MCL, R/R WM, R/R MZL, R/R FL, R/R RT, and R/R DLBCL will be enrolled to recieve the RDFE(s) identified in Phase 1 to further evaluate the safety and efficacy of BGB-16673.

Group II: Part 1f (Additional Monotherapy Safety Expansion in BTKi Naive B-Cell Malignancies) Experimental Treatment 1 Intervention

Participants with CLL/SLL, MCL, WM, MZL, or Richter's transformation to DLBCL who have not received a prior BTKi (either covalent or noncovalent) will be enrolled at selected dose levels.

Group III: Part 1e (Japan-only Cohort) Experimental Treatment 1 Intervention

Japanese participants with R/R MZL, FL, MCL, CLL/SLL, and WM will be enrolled at selected RDFE(s) to assess the safety and tolerability of BGB-16673.

Group IV: Part 1d (Additional Monotherapy Safety Expansion in R/R CLL/SLL) Experimental Treatment 1 Intervention

Participants with R/R CLL/SLL will be enrolled at selected RDFE(s) to generate additional safety and efficacy data for BGB-16673.

Group V: Part 1c (Additional Monotherapy Safety Expansion) Experimental Treatment 1 Intervention

Additional safety data will be collected from participants with R/R MZL, WM, RT, DLBCL, or FL to confirm the RDFE(s) of BGB-16673 for those with non-CLL/SLL/MCL histologies.

Group VI: Part 1b (Monotherapy Safety Expansion) Experimental Treatment 1 Intervention

Participants with R/R MZL, MCL, CLL/SLL, and WM will be enrolled at selected doses to help determine the recommended dose(s) for expansion (RDFE(s)) for BGB-16673.

Group VII: Part 1a (Monotherapy Dose Escalation) Experimental Treatment 1 Intervention

Dose escalation in specific subtypes of non-Hodgkin lymphoma (NHL), including relapsed or refractory (R/R) marginal zone lymphoma (MZL), relapsed or refractory (R/R) follicular lymphoma (FL) Grades 1, 2, and 3a, relapsed or refractory (R/R) mantle cell lymphoma (MCL), relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), relapsed or refractory (R/R) Richter's transformation (RT), and relapsed or refractory (R/R) Waldenström macroglobulinemia (WM), to evaluate the safety and tolerability of BGB-16673.

BGB-16673 is already approved in United States for the following indications:

Approved in United States as BGB-16673 for:

• Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) following 2 or more prior lines of therapy including a BTK inhibitor and a BCL-2 inhibitor

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a phase III trial, adding ibrutinib to R-CHOP chemotherapy significantly improved event-free survival in younger patients (≤60 years) with non-GCB diffuse large B cell lymphoma (DLBCL), achieving 100% survival in the MCD and N1 genetic subtypes.

Patients with the MCD and N1 subtypes who received only R-CHOP had much lower survival rates (42.9% and 50%, respectively), highlighting the importance of targeting chronic B cell receptor signaling with ibrutinib for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Wilson, WH., Wright, GW., Huang, DW., et al.[2022]

Ibrutinib, a BTK inhibitor, effectively reduces the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) in neuroblastoma (NB) models, leading to increased CD8+ T cell infiltration and decreased tumor growth.

The study shows that using ibrutinib in combination with anti-PDL1 checkpoint inhibitors enhances the antitumor immune response, suggesting a promising strategy for improving immunotherapy outcomes in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma. Ishfaq, M., Pham, T., Beaman, C., et al.[2023]

Chronic exposure to ibrutinib led to the development of resistant B-cell lines, which showed decreased levels of FOXO3a and PTEN and increased activation of AKT, indicating a mechanism of resistance to BTK inhibition.

Combining ibrutinib with the exportin 1 inhibitor selinexor restored the nuclear function of FOXO3a and PTEN, enhancing the effectiveness of ibrutinib and overcoming resistance, suggesting a potential new treatment strategy for B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies. Kapoor, I., Li, Y., Sharma, A., et al.[2021]

Ibrutinib is a first-in-class selective inhibitor of Bruton tyrosine kinase that shows promise in inhibiting the survival and proliferation of chronic lymphocytic leukemia (CLL) cells, based on preclinical studies.

Early clinical data indicate that ibrutinib may significantly impact CLL treatment, suggesting it could become a key part of therapy targeting the B-cell receptor signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. Jain, N., O'Brien, S.[2021]

Ibrutinib is a groundbreaking oral medication that specifically targets Bruton's tyrosine kinase, showing significant clinical benefits for patients with B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia, leading to rapid FDA approval for these conditions.

Unlike traditional chemotherapy, ibrutinib works by inhibiting B cell signaling pathways that are crucial for the survival and growth of cancer cells, representing a major shift in treatment strategies for B cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies. Gayko, U., Fung, M., Clow, F., et al.[2021]

Zanubrutinib, a Bruton's tyrosine kinase inhibitor, is primarily metabolized by the CYP3A enzyme, as shown by significant changes in its pharmacokinetics when coadministered with rifampin (a CYP3A inducer) and itraconazole (a CYP3A inhibitor).

The study demonstrated that the pharmacokinetics of zanubrutinib were consistent across Asian and non-Asian subjects, indicating that no dose adjustments are needed based on ethnicity, and the drug was well tolerated in participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. Mu, S., Tang, Z., Novotny, W., et al.[2022]

BTK inhibitors (BTKis) have significantly improved treatment for chronic lymphocytic leukemia (CLL) by targeting Bruton's tyrosine kinase, which is crucial for B-cell receptor signaling, leading to reduced cell proliferation and activation of harmful pathways.

While BTKis like ibrutinib and acalabrutinib are effective, they come with notable long-term adverse effects, including cardiac issues and infections, highlighting the need for careful management of these side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing toxicities of Bruton tyrosine kinase inhibitors. Lipsky, A., Lamanna, N.[2023]

Ibrutinib, a BTK inhibitor, has demonstrated excellent efficacy in treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) across various patient groups, including treatment-naïve and high-risk individuals.

As the use of ibrutinib increases, concerns about adverse events and drug resistance have arisen, leading to the exploration of new therapeutic targets and promising novel agents in early development to address these challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib. Kaur, V., Swami, A.[2021]

Zanubrutinib, a BTK inhibitor, demonstrated a 52.3% overall response rate in 44 Chinese patients with relapsed/refractory B-cell malignancies, indicating its potential effectiveness in treating these cancers.

The treatment was generally well tolerated, with the most common adverse event being a decrease in neutrophil count, and no serious complications like tumor lysis syndrome or new malignancies reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. Song, Y., Sun, M., Qi, J., et al.[2022]

Acalabrutinib, a second-generation BTK inhibitor, has demonstrated promising safety and efficacy in phase 1/2 clinical trials for patients with relapsed chronic lymphocytic leukemia (CLL) and pretreated mantle cell lymphoma (MCL).

The FDA has approved acalabrutinib for adult patients with MCL who have received at least one prior therapy, indicating its effectiveness as a treatment option, although further studies comparing it directly with ibrutinib and exploring combination therapies are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, A Second-Generation Bruton's Tyrosine Kinase Inhibitor. Kriegsmann, K., Kriegsmann, M., Witzens-Harig, M.[2019]

Ibrutinib is a highly effective and well-tolerated drug that inhibits Bruton's tyrosine kinase, leading to reduced B-cell activation and increased cancer cell death, particularly in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL).

The drug has received FDA approval for treating relapsed CLL and MCL, and ongoing research is exploring its use in other blood cancers and in combination with other therapies, indicating its potential for broader applications in hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase. Davids, MS., Brown, JR.[2021]

Ibrutinib has significantly improved chronic lymphocytic leukemia (CLL) treatment by providing durable responses with minimal myelosuppression, but relapses often occur due to mutations in BTK or PLCG2 that lead to resistance.

Patients with ibrutinib resistance may benefit from alternative therapies, such as the BCL2 inhibitor venetoclax or other agents targeting different pathways, as ongoing clinical trials explore combinations of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and alternative treatment strategies. Lama, TG., Kyung, D., O'Brien, S.[2021]

Orelabrutinib is a highly selective and irreversible BTK-inhibitor that has been approved in China for treating mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) in patients who have previously received treatment.

The drug is currently undergoing clinical development for various indications in both the USA and China, highlighting its potential as a therapeutic option for B cell malignancies and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orelabrutinib: First Approval. Dhillon, S.[2021]

References

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

Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies. [2021]

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

Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. [2021]

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

Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. [2022]

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

Managing toxicities of Bruton tyrosine kinase inhibitors. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib. [2021]

9. England pubmed.ncbi.nlm.nih.gov

A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Acalabrutinib, A Second-Generation Bruton's Tyrosine Kinase Inhibitor. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and alternative treatment strategies. [2021]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Orelabrutinib: First Approval. [2021]