A Study of Rocbrutinib in Combination With Lacutoclax in Patients With B-Cell Malignancies

Официальное название

A Phase Ib/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of BTK Inhibitor Rocbrutinib in Combination With BCL-2 Inhibitor Lacutoclax in Patients With B-Cell Malignancies

Обзор

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.

Вмешательства

• Препарат Lacutoclax+Rocbrutinib
  Phase 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 Rocbrut

Первичные конечные точки

• Phase Ib: Dose-limiting toxicity (DLT) [Срок оценки: At the end of Cycle 1 (the length of cycle 1 is 28 days)]
• Phase Ib: Maximum Tolerated Dose (MTD) [Срок оценки: At the end of Cycle 1 (the length of cycle 1 is 28 days)]
• Phase Ib: Adverse events as assessed by CTCAE v5.0 [Срок оценки: From the first administration to 28 days after the last administration]
• Phase Ib: Time to Maximum Plasma Concentration (Tmax) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase Ib: Maximum Plasma Concentration (Cmax) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase Ib: Area Under the Plasma Concentration-Time Curve from Time Zero to Time t (AUC0-t) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase Ib: Half-life (t1/2) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase II: Undetectable minimal residual disease (uMRD) rate assessed by flow cytometry [Срок оценки: Up to approximately three years]

Вторичные конечные точки (11)

• Phase II: Maximum Plasma Concentration (Cmax) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase II: Time to Maximum Plasma Concentration (Tmax) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase II: Area Under the Plasma Concentration-Time Curve from Time Zero to Time t (AUC0-t) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Phase II: Half-life (t1/2) [Срок оценки: From 1 hour prior to administration to 24 hours post-dose]
• Overall Response Rate(ORR) [Срок оценки: Up to approximately three years]
• Progression-free Survival(PFS) [Срок оценки: Up to approximately three years]
• Overall Survival(OS) [Срок оценки: Up to approximately three years]
• Phase II: Adverse events as assessed by CTCAE v5.0 [Срок оценки: From the first administration to 28 days after the last administration]
• Complete Response Rate (CRR) [Срок оценки: Up to approximately three years]
• Duration of Response (DOR) [Срок оценки: Up to approximately three years]
• Phase Ib: Undetectable Minimal Residual Disease (uMRD) Rate assessed by flow cytometry [Срок оценки: Up to approximately three years]

Критерии участия

Критерии включения

• 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.

II: For Treatment-naïve (TN) CLL/SLL patients: Must meet iwCLL treatment indications and no prior systemic therapy. For R/R CLL/SLL patients: at least one prior 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.
• Life expectancy ≥ 12 weeks.
• Adequate coagulation function, liver and kidney function, bone marrow hematopoietic function.
• Male patients and female patients of childbearing potential must agree to use effective contraception during the study and for 90 days after the last dose of study treatment. Female patients of childbearing potential must have a negative pregnancy test before study treatment and must not be breastfeeding. Male patients must not donate sperm during the study and for 90 days after the last dose.
• Participation is voluntary, requiring signed informed consent and compliance with the treatment regimen and visit schedule.

Критерии исключения

• 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.
• Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT), or autologous hematopoietic stem cell transplantation (auto-HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy within 90 days before the first dose of study treatment.
• Received antitumor therapy, investigational agents, major surgery, severe trauma, or live attenuated vaccines within 4 weeks or 5 half-lives prior to the first dose of study treatment.
• Received herbal medicines for antitumor treatment, or localized radiotherapy within 14 days prior to the first dose of study treatment.
• Use of moderate or strong CYP3A inhibitors within 7 days prior to the first dose of study treatment, or consumption of grapefruit, grapefruit juice, starfruit, or Seville oranges within 3 days prior to prior to the first dose.
• History of other active malignancies within the past 3 years, except for curatively treated basal cell carcinoma, localized squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other malignancies considered cured.
• Any severe and/or uncontrolled systemic disease, or any other condition that, in the opinion of the investigator, makes the patient unsuitable for participation in the study.
• Any of the following events within 6 months prior to the first dose: Symptomatic arrhythmia, myocardial infarction, intracranial hemorrhage, or Stroke.
• Impaired cardiac function.
• Any uncontrolled systemic infection.
• Conditions that may impair oral drug administration or significantly affect absorption or pharmacokinetics of the study drug.
• Unable to discontinue moderate or strong CYP3A inhibitors or inducers, P-gp (P-glycoprotein) inhibitors, sensitive substrates of OATP1B3 or CYP2C8 during the study period.
• Received vaccination with any live-attenuated vaccines within 4 weeks prior to the first dose of study treatment.
• Evidence of an active bleeding constitution or a history of significant hemorrhagic disorders.
• Requirement for ongoing therapy with warfarin or other vitamin K antagonists.
• Presence of an active, uncontrolled, or symptomatic autoimmune disease that requires systemic treatment.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for study participation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences — Тяньцзинь

Идентификаторы

NCT: NCT07609862 · LP-10822

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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