NCT05192486进行中（未招募）1 期
An Open-Label, Multi-Center, Phase Ib/II Study to Evaluate the Safety, Tolerability and Pharmacokinetic Characteristics of Tetra-specific Antibody GNC-038 in Participants With Recurrent or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 12
- 试验地点
- 4
- 主要终点
- Treatment-Emergent Adverse Event (TEAE)
研究概览
简要总结
In this study, the safety and preliminary efficacy of GNC-038 in participants with recurrent or refractory Diffuse Large B-cell lymphoma (DLBCL) will be investigated to assess the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) or maximum administered dose (MAD) for MTD is not reached of GNC-038. The recommended dose for phase II (RP2D) clinical study will also be determined.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 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
- •he participants could understand and sign the informed consent form, and must participate voluntarily;
- •No gender limit;
- •Age: ≥18 years old and ≤75 years;
- •Expected survival time ≥ 3 months;
- •Has suffered from Diffuse Large B-cell lymphoma (DLBCL) confirmed by histology or cytology;
- •a. Those who have recurrent or refractory Diffuse Large B-cell lymphoma (DLBCL).
- •b. Recurrent or refractory participants that are, determined by the investigators, not applicable/tolerated to other treatments.
- •Recurrent and refractory are defined as follows:
- •Recurrent is the progression of disease after adequate treatment to remission, with at least one regimen containing rituximab.
- •Refractory refers to failure to respond to adequate treatment with rituximab containing regimen (combination chemotherapy or monotherapy) or disease progression during treatment/within 6 months of completion of adequate treatment.
- •"Adequate treatment with rituximab regimen" refers to the completion of rituximab combined with chemotherapy based on pathological type and disease stage requirements, or rituximab monotherapy with 375 mg/m2 injections at least 4 times a week. "Progress during treatment" requires completion of at least one cycle of rituximab plus chemotherapy or monotherapy if progress during induction therapy; At least one injection is completed if progress is made during maintenance therapy. "Mitigation" includes complete and partial mitigation.
- •There are measurable lesions during the screening period (any long diameter of lymph node lesions ≥ 1.5 cm or any long diameter of extra-nodal lesions greater than 1.0 cm);
- •Physical fitness score ECOG≤2；
- •The toxicity of the previous anti-tumor therapy has been restored to the level ≤1 defined by NCI-CTCAE v5.0 (the investigators considered indicators that might be associated with the disease, such as anemia, and excluded toxicities that the investigators considered to be of no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stabilized by hormone replacement therapy);
- •The organ function within 7 days prior to the first administration meets the following requirements:
- •Bone marrow function: In the case of no blood transfusion, no use of G-CSF (no use of long-acting whitening needles within 2 weeks) and drug correction within 7 days prior to screening, the absolute value of neutrophil count (ANC) ≥1.0×109/L (participants with bone marrow infiltration ≥0.5×109/L); Hemoglobin ≥80 g/L (for participants with bone marrow infiltration, ≥70 g/L); Platelet count ≥50×109/L;
- •Liver function: In the absence of hepatoprotective drugs for correction within 7 days prior to screening, total bilirubin (TBIL) ≤ 1.5 ULN (TBIL ≤3 ULN in participants with Gilbert's syndrome), transaminase (AST/ALT) ≤ 2.5 ULN (participants with tumor infiltration in the liver ≤5.0 ULN);
- •Kidney function: creatinine (Cr) ≤ 1.5 ULN and creatinine clearance (Ccr) ≥ 50 mL/min (according to the Cockcroft and Gault formula);
- •Routine urine / 24h urine protein quantification: qualitative urine protein ≤1+ (if qualitative urine protein ≥2+, 24h urine protein < 1g can be included);
- •Cardiac function: left ventricular ejection fraction ≥50%;
- •Coagulation function: fibrinogen (FIB) ≥1.5g/L; activated partial thromboplastin time (APTT) ≤1.5×ULN; prothrombin time (PT) ≤1.5×ULN.
- •Female participants with fertility or male participants whose partner(s) are fertile must take effective contraceptive measures from 7 days prior to the first administration to 24 weeks after the administration. Female participants with fertility must have a negative serum/urine pregnancy test in 7 days prior to the first dose.
- •The subjects are able and willing to follow the visits, treatment plans, laboratory tests, and other study-related procedures specified in the study protocol.
排除标准
- •Has grade 3 or above lung disease defined according to NCI-CTCAE v5.0; Patients with current interstitial lung disease (ILD) (except those who have recovered from previous interstitial pneumonia;
- •Active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc;
- •Active tuberculosis;
- •Participants at risk of active autoimmune diseases, such as: systemic lupus erythematosus, systemic treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and hashimoto's thyroiditis, etc., with the exception of type I diabetes, only replacement therapy can control the hypothyroidism, no systemic treatment of skin disease (such as vitiligo, psoriasis), B cells caused by autoimmune disease;
- •Complicated with other malignant tumors within 5 years prior to GNC-038 treatment, except for non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer and localized prostate cancer that have been cured and have not recurred within 5 years;
- •HBsAg or HBcAb positive and HBV-DNA test ≥ULN; HCV antibody positive and HCV-RNA≥ULN; HIV antibody positive;
- •Participants with poorly controlled hypertension by antihypertensive drugs (systolic blood pressure>150 mmHg or diastolic blood pressure>100 mmHg);
- •History of severe heart disease, including but not limited to:
- •There are serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias, III grade atrioventricular block, which require clinical intervention;
- •Participants with prolonged QT interval (male QTc > 450 msec or female QTc > 470 msec);
- •Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or above cardiovascular and cerebrovascular events occurred within 6 months before the first administration;
- •New York Heart Association (NYHA) grade II, III or IV congestive heart failure;
- •Patients with a history of allergy to recombinant humanized antibodies or to any excipient component of GNC-038;
- •Pregnant or breastfeeding women;
- •There is an invasion of the central nervous system;
- •Has undergone major surgery within 28 days prior to the administration of this study, or planned to undergo major surgery during the study period (except for surgery such as puncture or lymph node biopsy);
- •Has accepted organ transplantation or allogeneic hematopoietic stem cell transplantation (ALLo-HSCT);
- •Has accepted autologous hematopoietic stem cell transplantation (Auto-HSCT) within 12 weeks prior to GNC-038 treatment;
- •Currently using immunosuppressive agents within 2 weeks prior to GNC-038 treatment, including but not limited to: Cyclosporine, tacrolimus, etc.; receiving high-dose glucocorticoids within 2 weeks prior to GNC-038 treatment (longer than 14 days, a stable dose of >30 mg of prednisone or other glucocorticoids at the same dose per day);
- •Has received radiotherapy within 4 weeks prior to GNC-038 treatment;
- •Has received anti-CD20 or anti-CD79b treatment within 4 weeks prior to GNC-038 treatment, and continued to respond;
- •Has received chemotherapy, small molecule targeted drugs within 2 weeks prior to GNC-038 treatment;
- •Has received CAR-T treatment within 12 weeks prior to GNC-038 treatment.
- •Has participated in any other clinical trials within 4 weeks prior to GNC-038 treatment;
- •Other conditions that the investigator believes that it is not suitable for participating in this clinical trial.
研究组 & 干预措施
Study treatment
Experimental
Participants receive GNC-038 as intravenous infusion for the first cycle (3 weeks). Participants with clinical benefit could receive additional treatment for more cycles. The administration will be terminated because of disease progression or intolerable toxicity occurring or other reasons.
干预措施: GNC-038 (Drug)
结局指标
主要结局
Treatment-Emergent Adverse Event (TEAE)
时间窗: Up to approximately 24 months
TEAE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally emerging, or any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition during the treatment of GNC-038. The type, frequency and severity of TEAE will be evaluated during the treatment of GNC-038.
Dose limiting toxicity (DLT)
时间窗: Up to 21 days after the first dose of GNC-038
The incidence and severity of adverse events during treatment were graded according to the National Cancer Institute Standard for Common Terminology for Adverse Events (NCI-CTCAE, v5.0).
The recommended dose for phase II clinical study（RP2D）
时间窗: Up to 21 days after the first dose of GNC-038
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for phase II study, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation study of GNC-038.
Maximum tolerated dose (MTD) or maximum administrated dose (MAD)
时间窗: Up to 21 days after the first dose of GNC-038
In the dose increment stage, the highest dose whose estimated DLT rate is closest to the target DLT rate but does not exceed the upper bound of the equivalent interval of DLT rate is selected as MTD.
次要结局
- ORR (Objective Response Rate )(Up to approximately 24 months)
- Adverse Events of special interest (AESI)(Up to approximately 24 months)
- Incidence and titer of ADA (Anti-drug antibody)(Up to approximately 24 months)
- Elimination half life （T1/2）(Up to 21 days after the first dose of GNC-038)
- Time to reach maximum concentration (Tmax)(Up to 21 days after the first dose of GNC-038)
- PFS (Progression-free Survival)(Up to approximately 24 months)
- CR (Complete Response)(Up to approximately 24 months)
- Peak Plasma Concentration（Cmax)(Up to 21 days after the first dose of GNC-038)
- Trough steady-state concentration（Css）(Up to 14 days after the first dose of GNC-038)
- AUC0-t(Up to 21 days after the first dose of GNC-038)
- Plasma clearance （CL）(Up to 21 days after the first dose of GNC-038)
- DCR (Disease Control Rate)(Up to approximately 24 months)
- DOR (Duration of Response)(Up to approximately 24 months)
- AUC0-inf(Up to 21 days after the first dose of GNC-038)
- Incidence and titer of Nab(Up to approximately 24 months)
研究者
研究点 (4)
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