MRD Guided Sonrotoclax and Zanubrutinib in Newly Diagnosed CLL/SLL

Official title

A Single Arm, Open-label Study of MRD-Guided Zanubrutinib in Combination With Sonrotoclax in Adult Patients With Treatment Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Overview

This is a single-arm, open-label study of sonrotoclax plus zanubrutinib with MRD-driven treatment duration in patients with previously untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The primary goal of this study is to evaluate the efficacy of MRD-guided zanubrutinib plus sonrotoclax for first-line CLL/SLL treatment.

Detailed description

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are often considered different variations of the same disease due to their many similarities. There is an urgent need for new treatments to improve patients' quality of life, prolong survival, and manage disease-related symptoms.

There are several different methods for treating front-line therapy, including Chemoimmunotherapy (CIT), Bruton tyrosine kinase inhibitors (BTKis), and BCL-2 inhibitors (BCL2is). Continuous treatment with BTK inhibitors is necessary for the treatment of CLL or SLL. However, younger patients may need to limit their therapeutic duration. The combination of BTK inhibitors and BCL-2 inhibitors is believed to be an optimizing regimen that provides a limited duration of therapy.

The main aim of this study is to assess whether MRD-guided zanubrutinib, in combination with sonrotoclax, can be an effective first-line treatment option for adult patients with treatment-naïve CLL or SLL. The goal is to achieve long-lasting and more profound responses, which could allow for the possibility of discontinuing treatment.

Interventions

• Drug Sonrotoclax
  Participants receive zanubrutinib orally 160mg bid from start of Cycle 1, and in combination with sonrotoclax (SZ) from Cycle 4 onwards at increasing doses until 320mg daily target dose is reached and continuing for at least 12 cycles (each cycle is 28 days). Participants with uMRD and PR/CR by the end of Cycle 15 will stop SZ treatment, others will continue to receive SZ for another 12 cycles and stop SZ if uMRD and PR/CR. Participants will receive sonrotoclax up to 2 years, and receive zanub
• Drug Zanubrutinib
  Participants receive zanubrutinib orally 160mg bid from start of Cycle 1,Participants with uMRD and PR/CR by the end of Cycle 15 will stop SZ treatment, others will continue to receive SZ for another 12 cycles and stop SZ if uMRD and PR/CR. Participants will receive sonrotoclax up to 2 years, and receive zanubrutinib for those with MRD-positive by then.

Primary outcome measures

• 4-Year Progressive Free Survival (PFS) Rate [Time frame: 4 years after enrollment]

Secondary outcome measures (8)

• Rate of peripheral blood (PB) and Bone marrow (BM) undetectable minimal residual disease (uMRD) [Time frame: At screening, the end of Cycle 14 and Cycle 26 (each cycle is 28 days)]
• Complete Response Rate (CRR; Complete Response/Complete Response with Incomplete Blood Count Recovery [CR/CRi]) Rate [Time frame: Up to 4 years]
• Overall Response Rate (ORR) [Time frame: Up to 4 years]
• Duration of Response (DOR) [Time frame: Up to 4 years]
• Progression Free Survival (PFS) [Time frame: Up to 4 years]
• Overall Survival (OS) [Time frame: Up to 4 years]
• Time to Next Therapy (TTNT) [Time frame: Up to 4 years]
• Overall survival rate [Time frame: Up to 4 years]

Eligibility criteria

Inclusion criteria

• Treatment naïve adult patients with diagnosis of CLL/SLL requiring treatment according to iwCLL guidelines 2018
• Measurable nodal disease by CT/MRI.
• Adequate hematologic function
• Adequate hepatic and renal function
• Eastern Cooperative Oncology Group
• (ECOG) performance status of 0-2
• Expected survival period > 6 months

Exclusion criteria

• Any prior systemic therapy used for treatment of CLL/SLL
• With history of prolymphocytic leukemia, known or currently suspected Richter's transformation
• Known central nervous system involvement by leukemia or lymphoma
• Confirmed progressive multifocal leukoencephalopathy (PML)
• Severe or debilitating pulmonary disease
• Clinically significant cardiovascular disease
• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura requiring treatment
• History of other malignancies
• Prior therapy with study drugs within 4 weeks before screening
• Active fungal, bacterial, and/or viral infection requiring systemic therapy
• Known allergy to zanubrutinib or sonrotoclax or any pharmaceutical excipients
• Pregnant or lactating women
• Vaccinated with live vaccines within 28 days prior to enrollment
• Serologically positive of human immunodeficiency virus (HIVAb), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
• History of stroke or intracranial hemorrhage within 6 months
• Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06367374 · BGB-11417-2002-IIT；BDH-CLL-004

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗