BTK inhibitors and BCL-2 inhibitors have demonstrated significant clinical activity in mature B-cell malignancies, and combination therapy may provide improved clinical benefit. This is a multi-center, open-label, single-arm Phase Ib/II clinical study. The purpose of this clinical trial is to investigate the safety, tolerability, pharmacokinetics, and preliminary efficacy of Rocbrutinib, a fourth-generation Bruton tyrosine kinase inhibitor (BTKi), in combination with the BCL-2 inhibitor Lacutoclax in patients with mature B-cell malignancies. The Phase Ib will use a classic 3+3 dose-escalation design to evaluate dose-limiting toxicities (DLTs), determine the maximum tolerated dose (MTD), and identify the recommended dosing regimen. The Phase II portion is intended to further evaluate the efficacy and safety of the combination therapy.
Age ≥18 years, regardless of sex.
Ib: Histologically confirmed diagnosis of CLL/SLL (per 2018 iwCLL criteria) or B-cell malignancies (per 2022 WHO classification), including: MCL, DLBCL, FL, and WM. Must have received at least one prior line of systemic therapy, with documented disease progression or intolerance.
Have at least one measurable lesion.
Phase Ib: ECOG performance status ≤1; phase II: ECOG performance status ≤2.
Known hypersensitivity or intolerance to Rocbrutinib, Lacutoclax, or any of their excipients; prior treatment with any BCL-2 inhibitor; or prior treatment with both covalent and non-covalent BTK inhibitors.
Use of systemic corticosteroids at doses equivalent to >20 mg/day of prednisone for ≥3 days within 7 days prior to the first dose.
History of or currently suspected Richter's syndrome.
Known or suspected central nervous system (CNS) involvement.
Single group
Lacutoclax+Rocbrutinib
DrugPhase Ib dose-escalation study of Rocbrutinib in combination with Lacutoclax. Rocbrutinib will be administered at a fixed dose of 150 mg once daily (QD), while Lacutoclax will be dose-escalated. Initial dose levels include Lacutoclax 200 mg QD and 400 mg QD in 28-day treatment cycles.Treatment will continue until disease progression, unacceptable toxicity/intolerance, or completion of the protocol-defined treatment duration, whichever occurs first. In phase II, participants will receive Rocbrutinib monotherapy for 8-12 weeks prior to combination treatment. Upon initiation of combination therapy, Lacutoclax will undergo dose ramp-up to the target dose and will then be administered continuously at the target dose. Treatment will continue until disease progression, unacceptable toxicity/intolerance, or completion of the protocol-defined treatment duration, whichever occurs first.
Phase Ib: Dose-limiting toxicity (DLT)
Phase Ib: Maximum Tolerated Dose (MTD)
Phase Ib: Adverse events as assessed by CTCAE v5.0
Phase Ib: Time to Maximum Plasma Concentration (Tmax)
Phase II: Maximum Plasma Concentration (Cmax)
Phase II: Time to Maximum Plasma Concentration (Tmax)
Phase II: Area Under the Plasma Concentration-Time Curve from Time Zero to Time t (AUC0-t)
Phase II: Half-life (t1/2)
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