BGB-16673 for B-Cell Cancers
(CaDAnCe-101 Trial)
Recruiting in Palo Alto (17 mi)
+133 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: BeiGene
Must be taking: BTK inhibitors
Must not be taking: Corticosteroids
Disqualifiers: Prior malignancy, CNS involvement, others
No Placebo Group
Approved in 1 Jurisdiction
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.
12345What 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.
678910How 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.
45111213Eligibility 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.
+2 more
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.
+2 more
Trial 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
Participant Groups
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.
7Treatment groups
Experimental Treatment
Group I: Phase 2 (Monotherapy Expansion)Experimental Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Nebraska Cancer SpecialistsOmaha, NE
Valkyrie Clinical Trials, Inc.Los Angeles, CA
Memorial Sloan Kettering Cancer CenterNew York, NY
Mayo Clinic (Rochester)Rochester, MN
More Trial Locations
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Who Is Running the Clinical Trial?
BeiGeneLead Sponsor
References
Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. [2022]In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.
BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma. [2023]MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.
Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies. [2021]Chronic activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling is a hallmark of many B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Ibrutinib, an FDA approved, orally administered BTK inhibitor, has demonstrated high response rates, however, complete responses are infrequent and acquired resistance to BTK inhibition can emerge. In this study, we generated ibrutinib-resistant (IB-R) cell lines by chronic exposure of CLL and activated B-cell (ABC)-DLBCL cells to ibrutinib in order to investigate the mechanism of acquired resistance to ibrutinib. IB-R cell lines demonstrated downregulation of FOXO3a and PTEN levels and activation of AKT, with their levels being low in the nuclei of resistant cells in comparison to the sensitive counterparts. Inhibition of PI3K and AKT using idelalisib and MK2206, respectively increased ibrutinib-induced apoptosis in IB-R cells by downregulation of pAKT473 and restoring FOXO3a levels, demonstrating the importance of these cell survival factors for ibrutinib-resistance. Notably, the exportin 1 inhibitor, selinexor synergized with ibrutinib in IB-R cells and restored nuclear abundance of FOXO3a and PTEN, suggesting that nuclear accumulation of FOXO3a and PTEN facilitates increase in ibrutinib-induced apoptosis in IB-R cells. These data demonstrate that reactivation of FOXO3a nuclear function enhances the efficacy of ibrutinib and overcomes acquired resistance to ibrutinib. Together, these findings reveal a novel mechanism that confers ibrutinib resistance via aberrant nuclear/cytoplasmic subcellular localization of FOXO3a and could be exploited by rational therapeutic combination regimens for effectively treating lymphoid malignancies.
Ibrutinib (PCI-32765) in chronic lymphocytic leukemia. [2021]B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are being studied as potential therapeutic targets. Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of Bruton tyrosine kinase. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation and affects CLL cell migration and homing. Early clinical data in patients with CLL and non-Hodgkin lymphoma is encouraging. It is likely that ibrutinib and other drugs targeting the BCR pathway will become an integral component of CLL therapy.
Development of the Bruton's tyrosine kinase inhibitor ibrutinib for B cell malignancies. [2021]Ibrutinib is a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase that has demonstrated clinical benefit for many patients with B cell malignancies. Positive results in initial trials led the U.S. Food and Drug Administration to grant ibrutinib three breakthrough therapy designations for mantle cell lymphoma (MCL), del17p chronic lymphocytic leukemia (CLL), and Waldenström's macroglobulinemia (WM). Ibrutinib was approved for these three cancers within 14 months of the original U.S. approval. Additionally, ibrutinib is approved for patient subsets with MCL and/or CLL in >45 other countries. Via a unique mechanism of action, ibrutinib inhibits B cell signaling pathways that regulate the survival, proliferation, adhesion, and homing of cancerous cells. This marks a paradigm shift from the conventional cytotoxic chemotherapy approach to treating B cell malignancies. Ibrutinib continues to be evaluated across a range of B cell malignancies, either as single-agent therapy or in combination with other therapies, and continues to transform the lives of these patients.
Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects. [2022]Zanubrutinib (BGB-3111) is a potent Bruton's tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown to be mainly metabolized through cytochrome P450 3A (CYP3A) in vitro. We evaluated the effect of steady-state rifampin (a strong CYP3A inducer) and steady-state itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics (PK), safety, and tolerability of zanubrutinib in healthy Asian and non-Asian subjects.
Managing toxicities of Bruton tyrosine kinase inhibitors. [2023]Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.
Ibrutinib in CLL: a focus on adverse events, resistance, and novel approaches beyond ibrutinib. [2021]Bruton's tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, heavily pre-treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge.
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]This single-arm, multicentre, phase I study is the first study of zanubrutinib, a potent, specific, irreversible Bruton tyrosine kinase (BTK) inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. The objectives were to evaluate safety and preliminary anti-tumour activity. Forty-four patients received zanubrutinib 320 mg once daily (QD) (n = 10) or 160 mg twice daily (BID) (n = 34) until disease progression or unacceptable toxicity. 29.5% of patients received zanubrutinib for at least two years. The most common adverse event (AE) and the most common grade 3 or higher AE was neutrophil count decreased (54.5% and 25.0% respectively). Two patients (4.5%) discontinued treatment due to AEs and one treatment-emergent AE led to death. All haemorrhagic events were grade 1-2 (except for one non-serious grade 3 purpura). No second primary malignancies, tumour lysis syndrome, or atrial fibrillation/flutter occurred. The overall response rate was 52.3% (complete response rate, 18.2%). Patients with all cancer subtypes benefited from treatment. BTK C481S/R or L528W mutations were found in zanubrutinib-progressive patients. The safety/efficacy profiles of patients treated with 320 mg QD and 160 mg BID were comparable and similar daily area under the curve (AUC) was achieved. Overall, zanubrutinib was well tolerated and either of these two regimens is clinically practical. Registered at ClinicalTrials.gov (NCT03189524, on 16 June 2017, https://clinicaltrials.gov/ct2/show/NCT03189524).
Acalabrutinib, A Second-Generation Bruton's Tyrosine Kinase Inhibitor. [2019]The Bruton's tyrosine kinase (BTK) is an essential in the B-cell receptor (BCR) signaling pathway which was identified as crucial in the pathogenesis of B-cell malignancies. Ibrutinib, a first-in-class BTK inhibitor, has been approved for the treatment of distinct B-cell malignancies. To overcome off-target side effects of and emerging resistances to ibrutinib, more selective second-generation BTK inhibitors were developed. Acalabrutinib is a novel second-generation BTK inhibitor and has shown promising safety and efficacy profiles in phase 1/2 clinical trials in patients with relapsed CLL and pretreated MCL. Recently, acalabrutinib was approved by the FDA for treatment of adult patients with MCL who received at least one prior therapy. However, clinical trials on a direct comparison between ibrutinib and acalabrutinib and on combination treatment options with other agents as CD20 antibodies are warranted.
Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase. [2021]Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor that is critical for B-cell survival and proliferation. In preclinical studies, ibrutinib bound to Bruton's tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clinical studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematologic malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and Waldenström's macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematologic malignancies.
Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and alternative treatment strategies. [2021]Development of the BTK inhibitor ibrutinib has changed the landscape of CLL treatment producing durable responses with minimal to no myelosuppression. Although remissions are durable, relapses remain a challenge.
Orelabrutinib: First Approval. [2021]Dysregulation of Bruton's tyrosine kinase (BTK) signalling has been linked to various B cell malignancies and autoimmune diseases. Orelabrutinib (®) is an orally administered, potent, irreversible and highly selective BTK-inhibitor being developed by InnoCare Pharma for the treatment of B cell malignancies and autoimmune diseases. In December 2020, orelabrutinib received its first approval in China for the treatment of patients with mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), who have received at least one treatment in the past. Clinical development of orelabrutinib for various indications is underway in the USA and China. This article summarizes the milestones in the development of orelabrutinib leading to this first approval.