NCT07159906

Homoharringtonine, BCL-2 Inhibitor, Rituximab, and Prednisone in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

A Phase Ib/II Prospective, Multicenter, Single-Arm Study of Homoharringtonine, BCL-2 Inhibitor, Rituximab and Prednisone in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

• Status: Not Yet Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 62 (estimated)
• Sponsor: First Affiliated Hospital of Zhejiang University · Academic / Other
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

Summary

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in China and worldwide. Although standard immunochemotherapy with Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine (Oncovin), and Prednisone (R-CHOP) achieves durable remissions in many patients, approximately 30-40% experience relapse or refractory disease with poor outcomes. Novel strategies are needed for patients who are not candidates for transplantation or who relapse after multiple lines of therapy. Homoharringtonine (HHT) is a natural cephalotaxine alkaloid extracted from Cephalotaxus species, clinically approved in China for acute and chronic myeloid leukemias. It inhibits ribosomal protein synthesis, modulates oncogenic and epigenetic signaling pathways, and induces apoptosis through mitochondrial and stress-activated pathways. Importantly, HHT downregulates the anti-apoptotic protein Myeloid Cell Leukemia 1 (MCL-1), a critical resistance factor to B-cell lymphoma 2 (BCL-2) inhibitors. This provides a strong mechanistic rationale for combining HHT with a BCL-2 inhibitor, together with rituximab and prednisone, in relapsed/refractory DLBCL. This prospective, multicenter, single-arm, Phase Ib/II study will evaluate the safety, tolerability, and efficacy of HHT, a BCL-2 inhibitor, rituximab, and prednisone in adult patients with relapsed/refractory DLBCL. Phase Ib will enroll 15-22 patients to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and the recommended phase II dose (RP2D) of HHT. Phase II will enroll 40 patients treated at RP2D to evaluate the overall response rate (ORR) after 3 and 6 cycles per Lugano 2014 criteria. Secondary endpoints include complete remission (CR), partial remission (PR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses will incorporate molecular biomarkers such as genomic profiling, circulating tumor DNA (ctDNA), and spatial transcriptomics.

Detailed description

This study is a prospective, multicenter, single-arm, Phase Ib/II clinical trial designed to evaluate the safety, tolerability, and efficacy of homoharringtonine (HHT), a B-cell lymphoma 2 (BCL-2) inhibitor, rituximab, and prednisone in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Despite the curative potential of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), approximately 30-40% of patients experience relapse or refractory disease, and outcomes remain poor, especially in those not eligible for transplantation or those relapsing after multiple prior therapies. Homoharringtonine is a cephalotaxine alkaloid approved in China for myeloid malignancies. It inhibits protein synthesis and downregulates Myeloid Cell Leukemia 1 (MCL-1), an important resistance factor to BCL-2 inhibition. Venetoclax (or Lisaftoclax, depending on study drug) is a selective oral BCL-2 inhibitor that restores apoptosis in tumor cells. Preclinical data demonstrate synergistic cytotoxicity when combining HHT with BCL-2 inhibition through complementary apoptotic mechanisms. Rituximab, an anti-CD20 monoclonal antibody, and prednisone, a glucocorticoid, further enhance anti-lymphoma activity and are established components of immunochemotherapy. Phase Ib will use a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and the recommended Phase II dose (RP2D) of HHT. Phase II will subsequently treat patients at the RP2D to assess overall response rate (ORR) as the primary efficacy endpoint, evaluated after 3 and 6 cycles according to Lugano 2014 criteria. Secondary endpoints include complete remission (CR), partial remission (PR), progression-free survival (PFS), overall survival (OS), and safety outcomes. Exploratory biomarker analyses will be performed to investigate predictors of treatment response. These include targeted gene sequencing, monitoring of circulating tumor DNA (ctDNA), and spatial transcriptomic profiling in selected patients. The findings are expected to provide important insights into the clinical potential of HHT combined with BCL-2 inhibition in relapsed/refractory DLBCL, and may inform the design of biomarker-guided treatment strategies in the future.

Conditions

• Diffuse Large B-Cell Lymphoma
• Relapsed Non-Hodgkin Lymphoma
• Refractory Non-Hodgkin Lymphoma

Interventions

Type	Name	Description
DRUG	Homoharringtonine	A cephalotaxine alkaloid and protein synthesis inhibitor that downregulates Myeloid Cell Leukemia 1 (MCL-1), administered intravenously in 21-day cycles. Dose escalation in Phase Ib will determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase II dose (RP2D).
DRUG	BCL-2 inhibitor	An oral selective BCL2 inhibitor administered once daily D1-7. Combined with homoharringtonine, rituximab, and prednisone in 21-day cycles.
DRUG	CD20 Antibody	An anti-CD20 monoclonal antibody administered intravenously, used in combination with chemotherapy or targeted regimens for B-cell malignancies.
DRUG	Glucocorticoid (GC)	glucocorticoid , given as part of the combination regimen to enhance anti-lymphoma effect.

Timeline

• Start date: 2025-09-08
• Primary completion: 2027-08-01
• Completion: 2028-08-01
• First posted: 2025-09-08
• Last updated: 2025-09-08

Locations

1 site across 1 country: China