NCT05008666Unknown2 期
Induction Chemotherapy Sequential Sintilimab Combined With Dual Epigenetic Drugs (Chidamide and Azacitidine) in ENKTL-HLH: A Single-arm, Multi-center, Phase II, Exploratory Clinical Study
Sun Yat-sen University1 个研究点 分布在 1 个国家目标入组 37 人开始时间: 2021年12月1日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Partial response rate (PRR) after end of treatment
研究概览
简要总结
ENKTL is a highly aggressive non-Hodgkin lymphoma closely related to EBV infection，and advanced patients often suffer from hemophagocytic lymphohistiocytosis (HLH). ENKTL-HLH lacks standard treatment and experiences a extremely poor prognosis. Anti-PD-1 antibody has shown good anti-tumor activity in ENKTL and play a potential role in EBV-HLH. Epigenetic drugs have been confirmed to exert synergistic anti-tumor activity with anti-PD-1 antibody. We next further explore the efficacy and safety of Sintilimab sequential combination of epigenetic drugs in ENKTL-HLH.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Volunteer to participate in clinical research; fully understand and know the research and sign the Informed Consent Form (ICF); willing to follow and have the ability to complete all trial procedures.
- •The age at the time of signing the ICF is ≥18 years old and ≤75 years old.
- •ENKTL confirmed by the research center histopathology and HLH conformed by the HLH-2004 diagnostic criteria.
- •Available tumor tissue samples (10-15 unstained, fresh-frozen, paraffin-embedded [FFPE] glass slides) obtained from past or fresh coarse needle puncture or excision.
- •Newly treated or refractory or relapsed ENKTL that has failed treatment with asparaginase-based chemotherapy or radiochemotherapy.
- •HLH occurred for the first time.
- •Eastern cooperative oncology group score:0-
- •Estimated survival≥3 months.
- •There must be at least 1 evaluable or measurable lesion that meets the RECIL 2017 lymphoma standard [evaluable lesion: 18FDG/PET examination Shows increased local uptake in lymph nodes or extranodal areas (higher than liver) and PET and/or Computed Tomography (CT) features are consistent with lymphoma manifestations; measurable lesions: nodular lesions longer than 15mm or extranodal lesions longer diameter >10mm (if the only measurable lesion has received radiotherapy in the past, there must be evidence of imaging progression after radiotherapy) and accompanied by increased 18FDG uptake]. No measurable lesion and the diffuse increased 18FDG uptake in the liver would be excluded.
- •Sufficient organ function, no serious heart, lung, kidney, thyroid dysfunction and immune deficiency:
- •Hemoglobin ≥6 g/dL (no growth factor support or blood transfusion was used within 7 days before platelet measurement);
- •Platelets ≥60×109/L (no growth factor support or blood transfusion was used within 7 days before platelet measurement);
- •Serum creatinine ≤1.5 times the upper limit of normal (Upper Limit Normal, ULN), or creatinine clearance ≥40mL/min (estimated according to the Cockcroft-Gault formula);
- •Serum total bilirubin ≤ 5 times ULN (unless it is confirmed to have Gilbert syndrome);
- •Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) ≤10 times ULN;
- •Coagulation function: International Normalized Ratio (INR)≤1.5 times ULN; Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT)≤1.5 times ULN; Fiber Fibrinogen (Fbg)>1.0g/L. (Unless the subject is receiving anticoagulant therapy and PT and APTT are within the expected range of anticoagulant therapy at the time of screening).
- •Thyroid stimulating hormone (TSH) or free thyroxine (FT4) or free triiodothyronine (FT3) are within ±10% of the normal value.
- •There is no evidence that the subject has difficulty breathing at rest, and the pulse oximetry value at rest is> 92%.
- •The subject must pass a pulmonary function test (PFT) to confirm that the forced expiratory volume (FEV1)/forced vital capacity (FVC) in the first second is greater than 60%; the diffusion volume of carbon monoxide (DLCO), FEV1 and FVC are all exceeding the predicted value by 50 % Above; all PFT results must be obtained within 4 weeks before the first dose.
- •Subjects who have received anti-tumor therapy in the past should return to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 rating score ≤ level 1 or baseline level after the toxicity of the previous treatment has been restored Entry into the group; The irreversible grade 2 toxicity (such as thrombocytopenia, anemia, neurotoxicity, hair loss and hearing loss) caused by previous anti-tumor treatments and is not expected to worsen during the study treatment period requires the consent of the investigator to be included in the group.
- •Women of Childbearing Potential (WOBCP) must have a serum pregnancy test within 7 days before the first medication, and the result is negative; WOBCP or men and their WOBCP partners should agree from signing the ICF to the last dose Take effective contraceptive measures within 6 months after the study drug.
排除标准
- •Invasive natural killer cell leukemia.
- •Primary central nervous system lymphoma or secondary central nervous system involvement.
- •Have received other anti-tumor therapy (including chemotherapy, immunotherapy, targeted therapy, and allowed to receive L-DEP or HLH-94/04 regimen for HLH).
- •Have received allogeneic organ transplantation.
- •Received allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 years before study drug administration (Patients who have received allo-HSCT more than 3 years before study drug administration and currently have no graft-versus-host reaction can be included in the group).
- •Participating in other clinical studies, or planning to start the treatment of this study is less than 4 weeks from the end of the previous clinical study.
- •An autologous hematopoietic stem cell transplantation(ASCT) was performed within 90 days.
- •Received immune checkpoint inhibitors (anti-PD-1/PD-L1/CTLA-4 antibodies and other drugs) within half a year.
- •Have received histone deacetylase inhibitor or DNA methyltransferase inhibitor treatment within 1 year before the study drug administration.
- •Suffer from active autoimmune diseases that require systemic treatment in the past two years (glucocorticoid replacement therapy is not considered systemic treatment, such as type I diabetes, hypothyroidism that requires only thyroxine replacement therapy, only Patients with low adrenal function or hypopituitarism who need to receive physiological doses of glucocorticoid replacement therapy); patients with autoimmune diseases who do not require systemic treatment in the past two years can be included in the group.
- •Subjects who need to receive systemic glucocorticoid therapy or other immunosuppressive therapy due to certain conditions within 14 days before starting the research treatment [Subjects are allowed to use topical, ocular, intra-articular, intranasal and inhaled types glucocorticoid therapy (very low systemic absorption); high-dose intravenous or oral glucocorticoid therapy for HLH is allowed; short-term (≤ 7 days) use of glucocorticoid for preventive treatment (such as contrast agent allergy) or for the treatment of non-autoimmune diseases (for example, delayed-type hypersensitivity reactions caused by contact allergens)].
- •Suffered from other malignant tumors in the past 5 years, except for skin basal cell carcinoma, skin squamous cell carcinoma, breast carcinoma in situ and cervical carcinoma in situ that have undergone radical treatment.
- •Received systemic anti-tumor therapy within 28 days before starting the study drug treatment, including chemotherapy, immunotherapy, biological therapy (tumor vaccine, cytokines, or growth factors), etc. [L-DEP or HLH-94/04 based regimens are allowed for HLH; G-CSF,IL-11, TPO, EPO therapy are allowed.
- •Received major surgery within 28 days or radiation therapy within 90 days.
- •Received traditional Chinese medicine or Chinese patent medicine treatment within 7 days.
- •Vaccine live vaccines (except influenza attenuated vaccine) within 28 days.
- •Human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome.
- •Patients with active chronic hepatitis B or active hepatitis C. In the screening period, patients who are positive for Hepatits B Surface Antigen (HBsAg) or Hepatitis C Virus (HCV) antibodies must pass the Hepatitis B Virus (HBV) DNA titer test (not allowed Higher than 2500 copies/mL or 500 IU/mL) and HCV RNA testing (not exceeding the lower limit of detection of the assay). After excluding the active hepatitis B or C infection that requires treatment, the test can be included . Carriers of hepatitis B virus, hepatitis B (DNA titer shall not be higher than 2500 copies/mL or 500 IU/mL) after drug treatment, and hepatitis C patients who have been cured can be included in the group.
- •Active tuberculosis.
- •Active fungal, bacterial and/or viral infections that require systemic treatment.
- •Women who are pregnant or breastfeeding.
- •People with a history of alcohol or drug abuse.
- •Suffer from uncontrollable comorbid diseases, including but not limited to symptomatic congestive heart failure, acute and chronic liver failure, uncontrollable hypertension, unstable angina, active peptic ulcer or bleeding disorders.
- •A history of interstitial lung disease or non-infectious pneumonia within 3 months before the start of the study treatment. Subjects who have previously had drug-induced or radioactive non-infectious pneumonia but asymptomatic are allowed to join the group.
- •QTcF interval> 450 msec, unless it is secondary to bundle branch block.
- •People with a history of mental illness; those who are incapacitated or restricted.
- •According to the judgment of the investigator, the patient's basic condition may increase the risk of receiving study drug treatment, or cause confusion about the toxic reaction and its judgment.
- •The investigator assessed that the patient was not suitable for participating in the study due to other conditions.
研究组 & 干预措施
L-DEP, Sintinimab+Chidamide, Sintinimab+Azacitidine
Experimental
【L-DEP】
L-asparaginase: 2000U/m2 d5, im
Doxorubicin liposome: 25mg/m2 d1, ivd
Etoposide: 100mg/m2 d1, d8, d15, ivd
Methylprednisolone: 15mg/kg/day d1-3, 0.75mg/kg/day, d4-7, 0.25mg/kg/day, d8-14, ivd
【Sintinimab+Chidamide】
Sintinimab: 200mg，d1,ivd,q21d Chidamide：30mg biw, continued oral
【Sintinimab+Azacitidine】
Sintinimab:200mg，d1, ivd, q21d Azacitidine:75mg/m2, d1-d7, ih, q28d
干预措施: Sintilimab (Drug)
L-DEP, Sintinimab+Chidamide, Sintinimab+Azacitidine
Experimental
【L-DEP】
L-asparaginase: 2000U/m2 d5, im
Doxorubicin liposome: 25mg/m2 d1, ivd
Etoposide: 100mg/m2 d1, d8, d15, ivd
Methylprednisolone: 15mg/kg/day d1-3, 0.75mg/kg/day, d4-7, 0.25mg/kg/day, d8-14, ivd
【Sintinimab+Chidamide】
Sintinimab: 200mg，d1,ivd,q21d Chidamide：30mg biw, continued oral
【Sintinimab+Azacitidine】
Sintinimab:200mg，d1, ivd, q21d Azacitidine:75mg/m2, d1-d7, ih, q28d
干预措施: Chidamide (Drug)
L-DEP, Sintinimab+Chidamide, Sintinimab+Azacitidine
Experimental
【L-DEP】
L-asparaginase: 2000U/m2 d5, im
Doxorubicin liposome: 25mg/m2 d1, ivd
Etoposide: 100mg/m2 d1, d8, d15, ivd
Methylprednisolone: 15mg/kg/day d1-3, 0.75mg/kg/day, d4-7, 0.25mg/kg/day, d8-14, ivd
【Sintinimab+Chidamide】
Sintinimab: 200mg，d1,ivd,q21d Chidamide：30mg biw, continued oral
【Sintinimab+Azacitidine】
Sintinimab:200mg，d1, ivd, q21d Azacitidine:75mg/m2, d1-d7, ih, q28d
干预措施: Azacitidine (Drug)
L-DEP, Sintinimab+Chidamide, Sintinimab+Azacitidine
Experimental
【L-DEP】
L-asparaginase: 2000U/m2 d5, im
Doxorubicin liposome: 25mg/m2 d1, ivd
Etoposide: 100mg/m2 d1, d8, d15, ivd
Methylprednisolone: 15mg/kg/day d1-3, 0.75mg/kg/day, d4-7, 0.25mg/kg/day, d8-14, ivd
【Sintinimab+Chidamide】
Sintinimab: 200mg，d1,ivd,q21d Chidamide：30mg biw, continued oral
【Sintinimab+Azacitidine】
Sintinimab:200mg，d1, ivd, q21d Azacitidine:75mg/m2, d1-d7, ih, q28d
干预措施: L-DEP (Drug)
结局指标
主要结局
Partial response rate (PRR) after end of treatment
时间窗: [Time Frame: up to 24 months]
Assessed by the lymphoma response to immunomodulatory therapy criteria (LYRIC)
Objective response rate (ORR) after end of treatment
时间窗: [Time Frame: up to 24 months]
Assessed by the lymphoma response to immunomodulatory therapy criteria (LYRIC)
Complete response rate (CRR) after end of treatment
时间窗: [Time Frame: up to 24 months]
Assessed by the lymphoma response to immunomodulatory therapy criteria (LYRIC)
次要结局
- Overall Survival (OS)([Time Frame: up to 36 months])
- Progression-Free Survival (PFS)([Time Frame: Time Frame: up to 36 months])
- Time to disease response (TTR)([Time Frame: up to 36 months])
- Duration of Response (DOR)([Time Frame: up to 36 months])
- Time to progression (TTP)([Time Frame: Up to 36 months])
- The frequency of adverse events (adverse events, AEs) and serious adverse events (SAEs)([Time Frame: Up to 36 months])
研究者
Huiqiang Huang
Professor
Sun Yat-sen University
研究点 (1)
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