Combination of Mitoxantrone Liposome and Etoposide, Dexamethasone, Pegaspargase and Golidocitinib (MEPL-G) in the Treatment of NK/T-cell Lymphoma Associated Hemophagocytic Lymphohistiocytosis (NKTCL-HLH): a Prospective, Multi-center, Single Arm, Phase Ib/II Clinical Trial
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- 6-month overall survival (OS) rate
研究概览
简要总结
Extranodal NK/T-cell lymphoma (NKTCL) is an aggressive EBV-associated lymphoma with poor prognosis, highly prevalent in China. Early-stage NKTCL achieves favorable long-term survival, while advanced disease shows dismal outcomes with no standard therapy. Notably, 10%-20% of patients develop secondary hemophagocytic lymphohistiocytosis (NKTCL-HLH), a life-threatening complication with median survival <2 months and mortality over 90%. Current treatments fail to simultaneously control lymphoma and hyperinflammation, with poor tolerance and high resistance.
The JAK/STAT pathway drives EBV-induced inflammation and tumor progression. Golidocitinib, a selective JAK1 inhibitor, demonstrates potent anti-NKTCL activity and rapid inflammation control. Liposomal mitoxantrone offers targeted efficacy with lower toxicity, while etoposide, methylprednisolone, and pegaspargase provide synergistic anti-tumor and anti-HLH effects.
This study proposes the novel MEPL-G regimen (liposomal mitoxantrone, etoposide, methylprednisolone, pegaspargase, golidocitinib) for NKTCL-HLH. By targeting both HLH and NKTCL, this combination aims to achieve rapid disease control, improve tolerance, and prolong survival, addressing the unmet critical clinical need for this high-risk population.
详细描述
Extranodal NK/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with particularly high incidence in Asia, especially in southern China where it accounts for 10%-15% of all malignant lymphomas. Early-stage NKTCL can achieve an 80% long-term survival rate with radiotherapy combined with pegaspargase-based chemotherapy. However, advanced and relapsed/refractory NKTCL carries a dismal prognosis, with long-term survival below 40%. A severe complication is hemophagocytic lymphohistiocytosis (HLH), which develops in 10%-20% of patients and leads to an extremely aggressive clinical course, with median survival less than 2 months and 6-month overall survival of only 23%.
Pathogenically, EBV infection induces abnormal immune activation through the JAK/STAT and NF-κB pathways, triggering a cytokine storm characterized by elevated IFN-γ, TNF-α, IL-6, and IL-10. This immune dysregulation, combined with impaired cytotoxic function, drives both lymphomagenesis and HLH progression. Current treatments remain unsatisfactory. Traditional HLH-directed regimens fail to control underlying lymphoma, while conventional lymphoma chemotherapy shows limited efficacy and poor tolerance due to multi-drug resistance and organ dysfunction.
Recently, targeted agents have emerged as promising strategies. Golidocitinib, a highly selective JAK1 inhibitor, effectively blocks JAK1-STAT3 signaling, suppresses EBV-driven tumor growth, and mitigates cytokine storms. It has demonstrated encouraging anti-tumor activity in relapsed/refractory NKTCL. Meanwhile, liposomal mitoxantrone improves tumor targeting and reduces cardiotoxicity, with objective response rates of 50%-60% in NKTCL. Etoposide, methylprednisolone, and pegaspargase further provide synergistic anti-lymphoma and anti-inflammatory effects.
Our research group has accumulated extensive experience in NKTCL and NKTCL-HLH, validating effective combination regimens and supporting the rationale of combining anti-lymphoma and anti-HLH strategies. Therefore, this study designed the innovative MEPL-G regimen (liposomal mitoxantrone, etoposide, methylprednisolone, pegaspargase, golidocitinib) for NKTCL-HLH patients. This regimen aims to rapidly control HLH, eradicate lymphoma, improve safety and tolerance, and ultimately prolong survival, addressing the urgent unmet medical need for this high-risk population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed extranodal NK/T-cell lymphoma.
- •Meeting the HLH-2004 diagnostic criteria (≥ 5 criteria).
- •Age ≥ 18 years, regardless of gender.
- •Negative HIV antigen or antibody.
- •Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac echocardiography.
- •No active visceral bleeding (e.g., gastrointestinal, pulmonary, cerebral).
- •No uncontrolled infection (e.g., pulmonary infection, intestinal infection).
- •Negative HCV antibody; or positive HCV antibody with negative HCV RNA.
- •Negative HBsAg and negative HBcAb. If either is positive, peripheral blood HBV DNA load must be < 1×10³ copies/mL to be eligible.
- •Signed written informed consent and ability to understand and comply with all study requirements.
排除标准
- •New York Heart Association (NYHA) cardiac function class ≥ II;
- •Female patients who are pregnant or breastfeeding;
- •Known hypersensitivity to any of the study drugs;
- •Presence of other concurrent malignancies (except non-melanoma skin cancer);
- •Concurrent central nervous system lymphoma infiltration;
- •Severe psychiatric disorders or inability to comply with follow-up;
- •Severe renal dysfunction (glomerular filtration rate < 15 mL/min);
- •Severe liver cirrhosis (MELD score > 20);
- •History of acute or chronic pancreatitis;
- •Simultaneous participation in another clinical trial.
研究组 & 干预措施
MEPL-G group
All enrolled patients may initiate induction therapy with the MEPL-G regimen after completing baseline imaging and laboratory examinations.
The detailed administration is as follows:
Doses of etoposide, golidocitinib, pegaspargase, and methylprednisolone are fixed. The optimal dose of liposomal mitoxantrone will be determined based on dose-limiting toxicity (DLT). In the Phase Ib part, 3 patients will be enrolled at the starting dose of liposomal mitoxantrone: 18 mg/m²/d on day 1, every 3 weeks (q3w). If no DLT occurs, the recommended phase 2 dose (RP2D) will be 18 mg/m²/d on day 1 q3w. If DLT occurs, the dose will be de-escalated sequentially. One cycle is 3 weeks, for a total of 6 cycles.
Patients achieving CR or PR after 2 cycles may be referred for allogeneic hematopoietic stem cell transplantation.
Patients with CR or PR after 2 cycles who are ineligible for transplantation may continue MEPL-G for a total of 6 cycles, followed by maintenance therapy with golidocitinib monotherapy
干预措施: Mitoxantrone liposome (Drug)
MEPL-G group
All enrolled patients may initiate induction therapy with the MEPL-G regimen after completing baseline imaging and laboratory examinations.
The detailed administration is as follows:
Doses of etoposide, golidocitinib, pegaspargase, and methylprednisolone are fixed. The optimal dose of liposomal mitoxantrone will be determined based on dose-limiting toxicity (DLT). In the Phase Ib part, 3 patients will be enrolled at the starting dose of liposomal mitoxantrone: 18 mg/m²/d on day 1, every 3 weeks (q3w). If no DLT occurs, the recommended phase 2 dose (RP2D) will be 18 mg/m²/d on day 1 q3w. If DLT occurs, the dose will be de-escalated sequentially. One cycle is 3 weeks, for a total of 6 cycles.
Patients achieving CR or PR after 2 cycles may be referred for allogeneic hematopoietic stem cell transplantation.
Patients with CR or PR after 2 cycles who are ineligible for transplantation may continue MEPL-G for a total of 6 cycles, followed by maintenance therapy with golidocitinib monotherapy
干预措施: Pegaspargase (PEG) Asparaginase (Drug)
MEPL-G group
All enrolled patients may initiate induction therapy with the MEPL-G regimen after completing baseline imaging and laboratory examinations.
The detailed administration is as follows:
Doses of etoposide, golidocitinib, pegaspargase, and methylprednisolone are fixed. The optimal dose of liposomal mitoxantrone will be determined based on dose-limiting toxicity (DLT). In the Phase Ib part, 3 patients will be enrolled at the starting dose of liposomal mitoxantrone: 18 mg/m²/d on day 1, every 3 weeks (q3w). If no DLT occurs, the recommended phase 2 dose (RP2D) will be 18 mg/m²/d on day 1 q3w. If DLT occurs, the dose will be de-escalated sequentially. One cycle is 3 weeks, for a total of 6 cycles.
Patients achieving CR or PR after 2 cycles may be referred for allogeneic hematopoietic stem cell transplantation.
Patients with CR or PR after 2 cycles who are ineligible for transplantation may continue MEPL-G for a total of 6 cycles, followed by maintenance therapy with golidocitinib monotherapy
干预措施: golidocitinib (Drug)
MEPL-G group
All enrolled patients may initiate induction therapy with the MEPL-G regimen after completing baseline imaging and laboratory examinations.
The detailed administration is as follows:
Doses of etoposide, golidocitinib, pegaspargase, and methylprednisolone are fixed. The optimal dose of liposomal mitoxantrone will be determined based on dose-limiting toxicity (DLT). In the Phase Ib part, 3 patients will be enrolled at the starting dose of liposomal mitoxantrone: 18 mg/m²/d on day 1, every 3 weeks (q3w). If no DLT occurs, the recommended phase 2 dose (RP2D) will be 18 mg/m²/d on day 1 q3w. If DLT occurs, the dose will be de-escalated sequentially. One cycle is 3 weeks, for a total of 6 cycles.
Patients achieving CR or PR after 2 cycles may be referred for allogeneic hematopoietic stem cell transplantation.
Patients with CR or PR after 2 cycles who are ineligible for transplantation may continue MEPL-G for a total of 6 cycles, followed by maintenance therapy with golidocitinib monotherapy
干预措施: Etoposide (Drug)
MEPL-G group
All enrolled patients may initiate induction therapy with the MEPL-G regimen after completing baseline imaging and laboratory examinations.
The detailed administration is as follows:
Doses of etoposide, golidocitinib, pegaspargase, and methylprednisolone are fixed. The optimal dose of liposomal mitoxantrone will be determined based on dose-limiting toxicity (DLT). In the Phase Ib part, 3 patients will be enrolled at the starting dose of liposomal mitoxantrone: 18 mg/m²/d on day 1, every 3 weeks (q3w). If no DLT occurs, the recommended phase 2 dose (RP2D) will be 18 mg/m²/d on day 1 q3w. If DLT occurs, the dose will be de-escalated sequentially. One cycle is 3 weeks, for a total of 6 cycles.
Patients achieving CR or PR after 2 cycles may be referred for allogeneic hematopoietic stem cell transplantation.
Patients with CR or PR after 2 cycles who are ineligible for transplantation may continue MEPL-G for a total of 6 cycles, followed by maintenance therapy with golidocitinib monotherapy
干预措施: methylprednisolone (Drug)
结局指标
主要结局
6-month overall survival (OS) rate
时间窗: From the date of initiation of MEPL-G as of 6 months after initiation of MEPL-G
OS was defined from the date of initiation of MEPL-G to the date fo death.
次要结局
- 6-month progression free survival (PFS) rate(From the date of initiation of MEPL-G as of 6 months after initiation of MEPL-G)
- overall response rate (ORR)(from the date of initiation of MEPL-G as of 6 months after initiation of MEPL-G.)
- complete response (CR) rate(from the date of initiation of MEPL-G as of 6 months after initiation of MEPL-G.)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability](from the date of initiation of MEPL-G as of 6 months after initiation of MEPL-G)
研究者
LIANG WANG
Director of Department of Hematology in Beijing Tongren Hospital
Beijing Tongren Hospital