A Study of GNC-038 Injection in Patients With Relapsed or Refractory NK/ T-cell Lymphoma, AITL, and Other NHL

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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NK/T Cell Lymphoma, Vascular Immunomother T Cell Lymphoma, Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: GNC-038


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 9. 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. Exclusion Criteria: 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 &gt;160 mmHg or diastolic blood pressure &gt;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-038. 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-038. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study treatment<br>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. | Drug: GNC-038<br>* Administration by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Dose Limited Toxicity (DLT) | 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). | Up to 16 days after the first dose | 
| Phase Ib: Maximum Tolerated dose (MTD) or maximum administered dose (MAD) | 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. | Up to 16 days after the first dose | 
| Phase Ib: Treatment-Emergent Adverse Event (TEAE) | 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. | Up to approximately 24 months | 
| Phase Ib: Recommended Phase II Dose (RP2D) | 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. | Up to 16 days after the first dose | 
| Phase II: Objective response rate (ORR) | 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. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Objective response rate (ORR) | 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. | Up to approximately 24 months | 
| Phase Ib: Progression-free survival (PFS) | The PFS is defined as the time from the participant's first dose of GNC-038 to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Phase Ib: Disease control rate (DCR) | The DCR is defined as the percentage of participants who has a CR, PR, or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD]). | Up to approximately 24 months | 
| Phase Ib:Duration of response (DOR) | The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Phase Ib: Complete Response (CR) | Disappearance of all target lesions. | Up to approximately 24 months | 
| Phase Ib: Adverse Events of Special Interest (AESI) | AESI is an event of scientific and medical interest specific to the sponsor's product or research project. | Up to approximately 24 months | 
| Phase Ib: Cmax | Maximum serum concentration (Cmax) of GNC-038 will be investigated. | Up to 16 days after the first dose | 
| Phase Ib:Tmax | Time to maximum serum concentration (Tmax) of GNC-038 will be investigated. | Up to 16 days after the first dose | 
| Phase Ib:AUC0-inf | Blood concentration - Area under time line. | Up to 16 days after the first dose | 
| Phase Ib: AUC0-T | Blood concentration - Area under time line. | Up to 16 days after the first dose | 
| Phase Ib: CL(Clearance) | To study the serum clearance rate of GNC-038 per unit time. | Up to 16 days after the first dose | 
| Phase Ib: T1/2 | Half-life (T1/2) of GNC-038 will be investigated. | Up to 16 days after the first dose | 
| Phase Ib: Anti-drug antibody (ADA) | Frequency and titer of anti-GNC-038 antibody (ADA) will be evaluated. | Up to approximately 24 months | 
| Phase II: Progression-free survival (PFS) | The PFS is defined as the time from the participant's first dose of GNC-038 to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Phase II: Disease control rate (DCR) | The DCR is defined as the percentage of participants who has a CR, PR, or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD]). | Up to approximately 24 months | 
| Phase II:Duration of response (DOR) | The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Phase II: Treatment-Emergent Adverse Event (TEAE) | 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. | Up to approximately 24 months |