Orelabrutinib Combined With Obinutuzumab and Short-Course Venetoclax in Patients With Treatment-Naïve Mantle Cell Lymphoma (MCL)

A Prospective, Multicenter, Open-label, Single-arm Phase II Clinical Study of Orelabrutinib in Combination With Obinutuzumab and Short-course Venetoclax in Patients With Treatment-naïve Mantle Cell Lymphoma (MCL)

This study aims to evaluate the safety and efficacy of orelabrutinib (O) in combination with obinutuzumab (G) and short-course venetoclax (V) in patients with treatment-naïve MCL.

Study Overview

• Status: Recruiting
• Conditions: Mantle Cell Lymphoma (MCL)
• Intervention / Treatment: Drug: Orelabrutinib; Drug: Obinutuzumab; Drug: Venetoclax

Detailed Description

MCL is difficult to cure, and the conventional treatment paradigm comprises a three-phase strategy: induction therapy based on intermediate- or high-dose cytarabine, consolidation with autologous stem cell transplantation (ASCT), and maintenance therapy with anti-CD20 monoclonal antibodies. Although this approach can yield long-term efficacy in young patients with MCL, it has notable limitations: it is less effective in patients with high-risk features such as a high Ki-67 index, TP53 mutations, or blastoid morphology, and elderly patients or those unfit for ASCT often cannot tolerate such intensive therapy.

Studies such as WINDOW-2 and BOVen have demonstrated that chemotherapy-free regimens combining a BTK inhibitor (BTKi), a BCL-2 inhibitor (BCL-2i), and an anti-CD20 monoclonal antibody are not limited by age and are equally effective in high-risk patients, making them a promising area of exploration for induction therapy in treatment-naïve MCL. However, the OASIS series of trials suggested that while the triplet regimen shows substantial efficacy and deeper responses in treatment-naïve MCL, it is also associated with a marked increase in adverse events (AEs). The safety concerns of triplet therapy should not be overlooked, and there is a need to explore novel therapeutic strategies that maintain efficacy while reducing the myelosuppression and treatment discontinuation rates associated with the addition of venetoclax.

This study aims to evaluate the safety and efficacy of orelabrutinib (O) in combination with obinutuzumab (G) and short-course venetoclax (V) in patients with treatment-naïve MCL. The induction phase consists of 6 cycles, in which venetoclax is introduced with dose ramp-up in Cycle 2 and subsequently administered for 14 days per cycle (thereby shortening the per-cycle exposure duration of venetoclax). This is followed by a maintenance phase in which orelabrutinib, obinutuzumab, and short-course venetoclax are continued up to Cycle 24. The primary endpoints are the complete response (CR) rate at the end of induction and the minimal residual disease (MRD) negativity rate assessed by immunoglobulin next-generation sequencing (IG-NGS) of plasma circulating tumor DNA (ctDNA). Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS), and the correlation between ctDNA MRD dynamics and clinical outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yi Xia; Phone Number: +8613770698391; Email: cynthia0311@163.com

Study Locations

• China
  • Jiangsu
    • Changzhou, Jiangsu, China
      • Recruiting
      • Changzhou Second People's Hospital
      • Contact: Xuzhang Lu; Phone Number: 86051988104931; Email: luxuzhang2008@163.com
    • Nanjing, Jiangsu, China, 210029
      • Recruiting
      • Jiangsu Province Hospital
      • Contact: Yi Xia; Phone Number: 86 25 86307573; Email: cynthia0311@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntarily participate and sign the informed consent form;
2. Age ≥ 18 years, male or female;
3. Life expectancy ≥ 3 months;
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Patients with ECOG 3 may be enrolled only if the decline in performance status is attributed to the underlying disease and the investigator determines that they may benefit from the treatment;
5. Pathologically confirmed diagnosis of mantle cell lymphoma (MCL) and treatment-naïve;
6. Presence of measurable and/or evaluable lymphoma lesions;
7. Adequate bone marrow reserve, defined as: absolute neutrophil count > 1.0×10⁹/L or platelet count > 75×10⁹/L, unless cytopenias are considered to be related to bone marrow involvement by lymphoma and deemed recoverable by the investigator;
8. Hepatic function: AST (SGOT) and ALT (SGPT) ≤ 2.5 × upper limit of normal (ULN) (in the absence of liver involvement) or ≤ 5 × ULN (in the presence of liver involvement); total bilirubin (TBIL) ≤ ULN; serum creatinine (CRE) ≤ 1.5 × ULN;
9. Creatinine clearance ≥ 30 mL/min, calculated using the Cockcroft-Gault formula;
10. Able to comply with the study visit schedule and other protocol requirements;
11. All patients of childbearing potential must agree to use effective contraceptive measures during the study and for 24 months after study treatment discontinuation. Female patients of childbearing potential must have a negative urine pregnancy test prior to the first dose of study treatment.

Exclusion Criteria:

1. Received prior treatment for lymphoma within 2 weeks before study enrollment;

2. Any serious medical condition, including but not limited to:

   • Uncontrolled hypertension (defined as blood pressure that remains uncontrolled after at least 4 weeks of treatment with a reasonable and tolerable regimen of 3 or more antihypertensive agents [including diuretics] at adequate doses, or requiring 4 or more antihypertensive agents to achieve adequate control);

     • Uncontrolled congestive heart failure within 6 months prior to screening (New York Heart Association [NYHA] Class III [moderate] or Class IV [severe] cardiac disease);

       • Left ventricular ejection fraction (LVEF) < 50%;

         • Symptomatic coronary artery disease (e.g., chest tightness, chest pain, palpitations, fatigue) or coronary artery disease requiring medical therapy; ⑤Severe bradycardia (heart rate < 40 beats per minute [bpm]) with hypotension, dizziness, or syncope; patients with a history of arrhythmia should undergo cardiac evaluation;

           • Known active bacterial, viral, fungal, or other infection (excluding fungal infection of the nail bed), or major infection within 2 weeks prior to the first dose of study drug;

             • Moderate to severe hepatic impairment (Child-Pugh Class B or C); ⑧Active bleeding within 2 months prior to screening, or clear evidence of bleeding diathesis as judged by the investigator; ⑨Current pulmonary disease that impairs lung function, such as pulmonary fibrosis or drug-related pneumonitis, which is deemed intolerable by the investigator; ⑩Any psychiatric or cognitive disorder that may limit the patient's ability to understand, execute, or comply with the informed consent and study requirements;
3. Known active hepatitis C virus (HCV) infection; or other acquired or congenital immunodeficiency disorders, including but not limited to human immunodeficiency virus (HIV) infection;
4. All patients with central nervous system (CNS) involvement by lymphoma;

5. Diagnosis of or receiving treatment for another malignancy other than lymphoma, except for the following:

   ①Malignancy that has been treated with curative intent and with no known active disease for ≥ 5 years prior to enrollment;

   ②Adequately treated basal cell carcinoma of the skin (excluding melanoma) with no evidence of disease;

   ③Adequately treated carcinoma in situ of the cervix with no evidence of disease;

6. Known hypersensitivity to any study drug;
7. Pregnant or breastfeeding women;
8. History of stroke or intracranial hemorrhage within 6 months prior to enrollment;
9. Requirement for anticoagulation therapy with warfarin or equivalent vitamin K antagonists;
10. Requirement for long-term treatment with strong cytochrome P450 3A (CYP3A) inhibitors;
11. Receipt of live attenuated vaccine within 4 weeks prior to enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: orelabrutinib (O) combined with obinutuzumab (G) and short-course venetoclax (V); Induction Phase (6 cycles, 28 days per cycle)： Orelabrutinib + Obinutuzumab + Venetoclax. Patients achieving partial response (PR) or complete response (CR) after 3 cycles will receive an additional 3 cycles of induction therapy.Patients with stable disease (SD) or progressive disease (PD) after 3 cycles will be withdrawn from the study.Patients achieving PR or CR at the end of induction will proceed to the maintenance phase (Cycles 7-24).Patients with SD or PD at the end of induction will be withdrawn from the study. Maintenance Phase (18 cycles, 28 days per cycle)： Orelabrutinib + Obinutuzumab + Venetoclax

Drug: Orelabrutinib; Orelabrutinib: 150 mg, d1-d28, C1-C6 (Induction Phase ) ; 150 mg, d1-d28, C7-C24 (Maintenance Phase); Drug: Obinutuzumab; Obinutuzumab: 1000 mg/m², on d1, d8, and d15 in C1; and on d1 in C2-C6 (Induction Phase ) ; 1000 mg/m², d1, once every 2 cycles, C7-C24 (Maintenance Phase); Drug: Venetoclax; Venetoclax: dose ramp-up in C2 (20 mg → 400 mg); 400 mg on d1-d14 in C3-C6(Induction Phase ) ; 400 mg, d1-d14, C7-C24(Maintenance Phase)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate (CRR)	The CRR is defined as the proportion of patients who achieve a CR following therapy, calculated among all treated patients.	At the end of induction therapy (6 cycles, 28 days per cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD negativity rate	The MRD negativity rate is defined as the proportion of patients who achieve MRD negativity in peripheral blood following treatment, calculated among all treated patients.	At the end of induction therapy (6 cycles, 28 days per cycle)
Objective response rate (ORR)	The objective response rate (ORR) is defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) after treatment, relative to the total treated population.	At the end of induction therapy (6 cycles, 28 days per cycle)
2-year progression-free survival (PFS)	PFS is defined as the time from registration to the first occurrence of progression or relapse as assessed by the investigator, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment.	From date of signing the informed consent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years
Overall Survival (OS)	Overall survival is defined as the period from the induction registration to death from any cause. Patients who have not died until the time of the analysis will be censored at their last contact date.	From date of signing the informed consent until the date of death from any cause, whichever came first (up to 3 years)
The occurrence of adverse events and serious adverse events	Adverse events will be graded by the investigator according to the NCI-CTCAE Version 5.0.	At the end of cycle 24 (28 days per cycle)

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Investigators: Principal Investigator: Yi Xia, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): July 15, 2026
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: July 17, 2026
• First Submitted That Met QC Criteria: July 21, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 21, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: MCL; venetoclax; obinutuzumab; orelabrutinib
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Mantle-Cell; venetoclax; obinutuzumab; orelabrutinib
• Other Study ID Numbers: 260608

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No