An Open, Multicenter, Phase Ib/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics/Pharmacokinetics, and Antitumor Activity of GNC-038 Injection in Relapsed or Refractory NK/ T-cell Lymphoma, AITL, and Other NHL
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 4
- 试验地点
- 2
- 主要终点
- Phase II: Objective response rate (ORR)
研究概览
简要总结
To explore the safety and efficacy of GNC-038 in relapsed or refractory NK/T cell lymphoma, vascular immunomother T cell lymphoma, and other relapsed or refractory NHL, and to determine MTD, MAD, DLT, and RP2D of GNC-038, as well as its pharmacokinetic characteristics and immunogenicity.
详细描述
Phase Ib: To explore the safety and preliminary effectiveness of GNC-038 under the administration mode of "intravenous infusion for 2h to 4h, once a week (IV, QW), 2 weeks as one cycle", and to determine MTD, MAD, DLT and RP2D of GNC-038. The pharmacokinetic characteristics and immunogenicity of GNC-038 will be evaluated. Phase II: To explore the efficacy, safety and tolerability, pharmacokinetic characteristics and immunogenicity of GNC-038.
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
- •Subjects can understand the informed consent, voluntarily participate in and sign the informed consent.
- •No gender restriction.
- •Age: ≥18 and ≤75 years old.
- •Expected survival time ≥3 months.
- •Patients with histologically confirmed NK/T cell lymphoma or vascular immunomother T cell lymphoma.
- •Patients with relapsed/refractory NK/T cell lymphoma (R/R NKTCL) or relapsed/refractory vascular immunomother T cell lymphoma (AITL):
- •1) Patients with recurrent or refractory vascular immunomother T cell lymphoma after initial treatment.
- •2) Patients with NK/T cell lymphoma need to have received systematic therapy with asparaginase regimen in the past, and have received radiotherapy for single lesion recurrence or refractory treatment.
- •Difficult-to-treat definition: i) the curative effect of end-line treatment did not reach PR; Or ii) disease progression within 6 months after terminal line treatment.
- •7. In the screening period, there were measurable lesions (lymph node lesions with any length ≥1.5cm or exodal lesions with any length > 1.0cm, all of which had metabolic activity).
- •8. Physical status score ECOG ≤2 points.
- •The adverse reactions of previous antitumor therapy were restored to CTCAE level 5.0 evaluation ≤ level 1 (except for indicators that the researchers considered might be related to the disease, such as anemia, and toxicities that the researchers judged to have no safety risk, such as hair loss, grade 2 peripheral neurotoxicity, stable hypothyroidism after hormone replacement therapy, etc.).
- •10. Organ function level before initial administration meets the following requirements: Bone marrow function: without blood transfusion within 7 days prior to screening, without G-CSF (without long-acting rising white needle within 2 weeks) and drug correction: Absolute neutrophil count (ANC) ≥1.0×109/L (≥0.5×109/L for subjects with bone marrow infiltration); Hemoglobin ≥80 g/L (≥70g/L for subjects with bone marrow infiltration); Platelet count ≥75×109/L; Liver function: total bilirubin ≤1.5 ULN (Gilbert's syndrome ≤3 ULN), transaminase (AST/ALT) ≤2.5 ULN (subjects with liver tumor invasive changes ≤5.0 ULN) within 7 days before screening without liver protection drugs; Renal function: creatinine (Cr) ≤1.5 ULN and creatinine clearance (Ccr) ≥50 ml/min (according to Cockcroft and Gault formula); Urine routine /24 hours urine protein quantification: qualitative urine protein ≤1+ (if qualitative urine protein ≥2+, 24 hours urine protein < 1g can be included in the group); Cardiac function: left ventricular ejection fraction ≥50%; Coagulation function: fibrinogen ≥1.5g/L; Activated partial thrombin time (APTT) ≤1.5 ULN; Prothrombin time (PT) ≤1.5 ULN.
- •11. Fertile female subjects or fertile male subjects with partners must use highly effective contraception from 7 days prior to the first dose until 12 weeks after termination of treatment. A fertile female subject must have a negative serum/urine pregnancy test within 7 days prior to initial dosing.
- •12. Subject is able and willing to comply with visits, treatment plans, laboratory tests, and other study-related procedures as specified in the study protocol.
排除标准
- •According to NCI-CTCAE v5.0, it was defined as ≥ grade 3 pulmonary disease; Patients who currently have interstitial lung disease (ILD) (except those who previously had interstitial pneumonia and have recovered).
- •Active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc.
- •Active tuberculosis.
- •Patients with hemophagocytic syndrome.
- •Patients with lesions invading pulmonary great vessels.
- •Active patients with 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 (e.g., vitiligo, psoriasis), B cells caused by autoimmune disease.
- •Non-melanoma skin cancer in situ, superficial bladder cancer in situ, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer, localized prostate cancer and other malignant tumors that were combined with other malignant tumors within 5 years prior to the first administration of the drug, except those that the researchers thought could be included.
- •HBsAg positive or HBcAb positive, and HBV-DNA detection ≥ detection value lower limit (HBV-DNA detection in the normal range and regular use of anti-HBV drugs except patients); HCV antibody was positive and HCV-RNA≥ lower limit of detection value.
- •Poorly controlled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg).
- •A history of severe cardiovascular and cerebrovascular diseases, including but not limited to:
- •Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias and degree III atrioventricular block that require clinical intervention; Prolonged QT interval at rest (QTc > 450 msec in men or 470 msec in women); Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurring within 6 months prior to initial administration; Present with heart failure ≥II on the New York Heart Association (NYHA) cardiac function scale.
- •Patients with a history of allergy to recombinant humanized antibodies or to any excipient component of GNC-
- •Pregnant or breastfeeding women.
- •Patients with central nervous system invasion.
- •Patients who received major surgery within 28 days prior to drug administration in this study, or planned to undergo major surgery during the study period (except for procedures such as puncture or lymph node biopsy).
- •Previous recipients of organ transplantation or allogeneic hematopoietic stem cell transplantation (Allo-HSCT).
- •Autologous hematopoietic stem cell transplantation (Auto-HSCT) within 24 weeks before starting GNC-038 therapy.
- •Immunosuppressants are being used, including, but not limited to, cyclosporine, tacrolimus, etc. within 2 weeks prior to treatment with GNC-
- •Radiotherapy was received within 4 weeks prior to the initiation of GNC-038 therapy.
- •Received chemotherapy and small molecule targeted therapy within 2 weeks prior to treatment.
- •Received CAR-T therapy within 12 weeks prior to initiation of GNC-038 therapy.
- •Participants in any other clinical trial within 4 weeks prior to administration of this trial.
- •A history of immunodeficiency, including HIV positive testing, or other acquired, congenital immunodeficiency diseases.
- •Other conditions deemed unsuitable for participation in this clinical trial by the investigator.
研究组 & 干预措施
Study treatment
Participants receive GNC-038 as intravenous infusion for the first cycle (2 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
Phase II: Objective response rate (ORR)
时间窗: Up to approximately 24 months
ORR is defined as the percentage of participants, who has a CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experiences a confirmed CR or PR is according to RECIST 1.1.
Phase Ib: Maximum Tolerated dose (MTD) or maximum administered dose (MAD)
时间窗: Up to 16 days after the first dose
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.
Phase Ib: 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.
Phase Ib: Recommended Phase II Dose (RP2D)
时间窗: Up to 16 days after the first dose
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.
Phase Ib: Dose Limited Toxicity (DLT)
时间窗: Up to 16 days after the first dose
The incidence and severity of adverse events (TEAE) during treatment were graded according to the National Cancer Institute Standard for Common Terminology for Adverse Events (NCI-CTCAE, v5.0).
次要结局
- Phase Ib: Objective response rate (ORR)(Up to approximately 24 months)
- Phase Ib: Complete Response (CR)(Up to approximately 24 months)
- Phase Ib: Adverse Events of Special Interest (AESI)(Up to approximately 24 months)
- Phase Ib:Tmax(Up to 16 days after the first dose)
- Phase Ib: Progression-free survival (PFS)(Up to approximately 24 months)
- Phase Ib:Duration of response (DOR)(Up to approximately 24 months)
- Phase Ib: Disease control rate (DCR)(Up to approximately 24 months)
- Phase Ib: Cmax(Up to 16 days after the first dose)
- Phase Ib:AUC0-inf(Up to 16 days after the first dose)
- Phase Ib: AUC0-T(Up to 16 days after the first dose)
- Phase Ib: CL(Clearance)(Up to 16 days after the first dose)
- Phase Ib: T1/2(Up to 16 days after the first dose)
- Phase Ib: Anti-drug antibody (ADA)(Up to approximately 24 months)
- Phase II: Progression-free survival (PFS)(Up to approximately 24 months)
- Phase II: Disease control rate (DCR)(Up to approximately 24 months)
- Phase II:Duration of response (DOR)(Up to approximately 24 months)
- Phase II: Treatment-Emergent Adverse Event (TEAE)(Up to approximately 24 months)