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

NCT07159906 · tracked via the Priya Life Science China tracker

Sponsor

First Affiliated Hospital of Zhejiang University

Phase

Phase 1/2

Started

2025-09-08

Last updated

2025-09-08

Condition(s) studied

Diffuse Large B-Cell LymphomaRelapsed Non-Hodgkin LymphomaRefractory Non-Hodgkin Lymphoma

Investigational drug(s) / intervention(s)

Homoharringtonine →BCL-2 inhibitor →CD20 Antibody →Glucocorticoid (GC) →

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).

BCL-2 inhibitor: An oral selective BCL2 inhibitor administered once daily D1-7. Combined with homoharringtonine, rituximab, and prednisone in 21-day cycles.

CD20 Antibody: An anti-CD20 monoclonal antibody administered intravenously, used in combination with chemotherapy or targeted regimens for B-cell malignancies.

Glucocorticoid (GC): glucocorticoid , given as part of the combination regimen to enhance anti-lymphoma effect.

Study 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.

Eligibility

Sex

ALL

Min age

18 Years

Max age

99 Years

Healthy volunteers

Phase II Inclusion Criteria 1. Histopathologically confirmed CD20-positive diffuse large B-cell lymphoma; 2. Age ≥18 years at enrollment, regardless of gender, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3; 3. Disease is refractory to or progresses within one year after first-line standard therapy containing anti-CD20 monoclonal antibodies and anthracycline-based chemotherapy, or has failed or relapsed after second-line or later standard treatment regimens, or has relapsed after autologous hematopoietic stem cell transplantation (more than 6 months post-transplant); 4. At least one measurable lesion present (as defined by the Lugano 2014 response criteria: measurable lesion is defined as a lymph node lesion with a longest diameter \>1.5 cm on CT axial imaging, or an extranodal lesion with a longest diameter \>1.0 cm, and 18F-FDG PET/CT positive lesion); 5. Able to provide written informed consent and capable of understanding and complying with all study requirements. Phase II Exclusion Criteria 1. Patients with poor compliance or inability to attend regular follow-up visits; 2. Presence of severe organ dysfunction, as judged by the investigator, that renders the patient unsuitable for participation in this trial; 3. Absolute neutrophil count \< 1.0 × 10⁹/L, platelet count \< 50 × 10⁹/L, or hemoglobin \< 80 g/L (excluding cases due to lymphoma bone marrow infiltration); 4. Other factors, as determined by the investigator, that may lead to forced early withdrawal from the study, such as other serious medical conditions (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, or family/social factors that may affect patient safety or compliance; 5. History of immunodeficiency, including HIV-positive status, or other acquired or congenital immunodeficiency diseases; 6. Pregnant or breastfeeding women, and fertile patients unwilling to use contraception. 7. Acute or chronic active hepatitis B or C infection, with HBV DNA \> 2000 IU/mL or 10⁴ copies/mL, or HCV RNA \> 10³ copies/mL; 8. Central nervous system (CNS) metastases; however, patients with asymptomatic CNS metastases or those with symptoms that have been treated and stabilized for ≥4 weeks may be eligible; 9. Prior history of allogeneic hematopoietic stem cell transplantation; 10. Cardiac dysfunction: baseline Corrected QT interval (QTc) ≥ 500 ms; Left Ventricular Ejection Fraction (LVEF) \< 45%, or New York Heart Association (NYHA) classification Class III/IV heart failure; 11. Known severe hypersensitivity to benzyl alcohol or any other components of the study drugs; 12. Requirement for concomitant use of strong CYP3A4 inducers due to medical necessity.

Primary outcome measure(s)

Dose-Limiting Toxicities (DLT) — Cycle 1 (first 21-day cycle)
Incidence of dose-limiting toxicities assessed during Cycle 1, according to NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Maximum Tolerated Dose (MTD) — End of Phase Ib dose-escalation
The highest dose level at which ≤1 out of 6 patients experience a DLT, determined during dose-escalation phase.
Recommended Phase II Dose (RP2D) — End of Phase Ib dose-escalation
RP2D determined based on DLT, MTD, safety, and preliminary efficacy findings in Phase Ib.
Overall Response Rate (ORR) — At Cycle 3 and Cycle 6
Proportion of patients achieving CR or PR, assessed per Lugano 2014 criteria using Positron Emission Tomography-Computed Tomography (PET-CT) or Computed Tomography (CT).

Trial sites (1)

Facility	City	Region	Status
Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University	Hangzhou	Zhejiang

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Official registry record

This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.

View NCT07159906 on ClinicalTrials.gov ↗ ← All trials in China