Ignite Creation Date:
2025-12-26 @ 5:19 PM
Ignite Modification Date:
2025-12-31 @ 9:58 PM
Study NCT ID:
NCT07159906
Status:
NOT_YET_RECRUITING
Last Update Posted:
2025-09-08
First Post:
2025-08-17
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Homoharringtonine, BCL-2 Inhibitor, Rituximab, and Prednisone in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Sponsor:
First Affiliated Hospital of Zhejiang University
Organization:
Study Overview
Official Title:
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
Status Verified Date:
2025-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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.
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.
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.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: