Phase Ib/II Study of GNC-038 Injection in Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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To explore the safety and preliminary efficacy of GNC-038 in patients with relapsed or refractory NHL, and to determine the MTD and RP2D of GNC-038, or the MAD and DLT

Detailed Description
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phase Ib: To explore the safety and preliminary efficacy of GNC-038 in patients with relapsed or refractory NHL, and to determine the MTD and RP2Dof GNC-038, or the MAD and DLT of GNC-038 if MTD is not reached, by intravenous infusion (IV, QW) once a week (2 weeks as a cycle) phase II To explore the efficacy of GNC-038 in patients with relapsed or refractory non-Hodgkin's lymphoma

Official Title
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An Open, Multicenter, Phase Ib/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of Tetra-specific Antibody GNC-038 Injection in Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL)

Conditions
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Non-hodgkin's Lymphoma

Intervention / Treatment
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* Drug: GNC-038


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. The subject can understand the informed consent form, voluntarily participate in and sign the informed consent form; 2. Both sexes; 3. Age: ≥18 years and ≤75 years; 4. Expected survival time ≥3 months; 5. Patients with histologically confirmed non-Hodgkin's lymphoma; 6. Patients with relapsed and refractory non-Hodgkin's lymphoma (R/R NHL). Specifically include: Patients who have experienced at least a second-line treatment failure; Investigator-determined patients with relapsed or refractory non-Hodgkin's lymphoma who had no or were ineligible/intolerant to other therapies. 7. The presence of measurable lesions (any length diameter of lymph node lesions ≥1.5cm or any length diameter of extranodal lesions > 1.0cm) during the screening period; 8. ECOG score ≤2; 9. Adverse reactions of previous antitumor therapy returned to CTCAE 5.0 grade ≤1 (except for indicators that the investigator considered to be related to the disease, such as anemia, and toxicity that the investigator judged to be of no safety risk, such as hair loss, grade 2 peripheral neurotoxicity, and stable hypothyroidism after hormone replacement therapy); 10. The organ function level before the first administration met the following requirements: Bone marrow function: In the absence of blood transfusion within 7 days prior to screening, G-CSF (no long-acting white needle within 2 weeks), and medication correction: Absolute neutrophil count (ANC) ≥1.0×10^9/L (≥0.5×10^9/L for subjects with bone marrow infiltration); Hemoglobin ≥80 g/L (≥70g/L for subjects with bone marrow infiltration); Platelet count ≥75×10^9/L; Liver function: Total bilirubin ≤1.5 ULN (≤3 ULN for Gilbert's syndrome) and transaminase (AST/ALT) ≤2.5 ULN (≤5.0 ULN for subjects with tumor invasive changes in the liver) without correction with hepatoprotective agents within 7 days before screening; Kidney function: creatinine (Cr) ≤1.5 ULN and creatinine clearance (Ccr) ≥50 ml/min (according to Cockcroft and Gault formula); Urine routine / 24-hour urinary protein quantification: urine protein qualitative ≤1+ (if urine protein qualitative ≥2+, 24-hour urinary protein < 1g can be enrolled); Cardiac function: left ventricular ejection fraction ≥50%; Coagulation function: fibrinogen ≥1.5g/L; Activated partial thromboplastin time (APTT) ≤1.5 ULN; Prothrombin time (PT) ≤1.5 ULN. 11. Fertile female subjects or male subjects with a fertile partner must use highly effective contraception from 7 days before the first dose until 12 weeks after discontinuation of treatment. Fertile female subjects must have a negative serum/urine pregnancy test within 7 days before the first dose; 12. Subjects are able and willing to comply with the study protocol for visits, treatment plans, laboratory tests, and other study-related procedures. Exclusion Criteria: 1. Pulmonary disease grade ≥3 as defined by NCI-CTCAE V5.0; Patients with current interstitial lung disease (ILD) (except those who have recovered from previous interstitial pneumonia); 2. Active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc.; 3. Active pulmonary tuberculosis; 4. Patients with 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 (e.g., vitiligo, psoriasis), B cells caused by autoimmune disease; 5. Other malignant tumors were complicated within 5 years before the first administration, except non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer, localized prostate cancer that had been cured and had not recurred within 5 years. 6. HBsAg positive or HBcAb positive, and HBV-DNA detection ≥ the lower limit of the detection value; HCV antibody positive and HCV-RNA≥ lower limit of detection value; HIV antibody positive; 7. Poorly controlled hypertension (systolic blood pressure & GT; 160 mmHg or diastolic blood pressure & GT; 100 mmHg); 8. History of serious cardiovascular and cerebrovascular diseases, including but not limited to: Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, degree ⅲ atrioventricular block, etc.; At rest, the QT interval is prolonged (QTc > 450 msec in men or QTc > 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 before the first dose; The presence of New York Heart Association (NYHA) class II or higher heart failure; 9. Patients with a history of allergy to recombinant humanized antibodies or to any excipient components of GNC-038; 10. Women who are pregnant or breastfeeding; 11. Patients with central nervous system invasion; 12. Patients who underwent major surgery within 28 days before the administration of the drug in this study, or who were to undergo major surgery during the study period (except for puncture or lymph node biopsy); 13. Previous organ transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT); 14. Autologous hematopoietic stem cell transplantation (Auto-HSCT) was performed within 12 weeks before starting GNC-038 treatment. 15. Pulmonary disease grade ≥3 as defined by NCI-CTCAE V5.0; Patients with current interstitial lung disease (ILD) (except those who have recovered from previous interstitial pneumonia); 16. Active infections that require systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc.; 17. Active pulmonary tuberculosis; 18. Patients with 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 (e.g., vitiligo, psoriasis), B cells caused by autoimmune disease; 19. Other malignant tumors were complicated within 5 years before the first administration, except non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer, localized prostate cancer that had been cured and had not recurred within 5 years. 20. HBsAg positive or HBcAb positive, and HBV-DNA detection ≥ the lower limit of the detection value; HCV antibody positive and HCV-RNA≥ lower limit of detection value; HIV antibody positive; 21. Poorly controlled hypertension (systolic blood pressure & GT; 160 mmHg or diastolic blood pressure & GT; 100 mmHg); 22. A history of serious cardiovascular and cerebrovascular diseases, including but not limited to: 23. Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, degree ⅲ atrioventricular block, etc.; 24. At rest, the QT interval was prolonged (QTc > 450 msec in men or QTc > 470 msec in women). 25. Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before the first dose; 26. The presence of New York Heart Association (NYHA) heart failure grade II or higher; 27. Patients with a history of allergy to recombinant humanized antibodies or to any excipient component of GNC-038; 28. Women who are pregnant or breastfeeding; 29. Patients with central nervous system invasion; 30. Patients who underwent major surgery within 28 days before the administration of the drug in this study, or who were to undergo major surgery during the study period (except for puncture or lymph node biopsy); 31. Previous recipients of organ transplantation or allogeneic hematopoietic stem cell transplantation (allo-HSCT); 32. Autologous hematopoietic stem cell transplantation (Auto-HSCT) was performed within 12 weeks before starting GNC-038 treatment.

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 |
| --- | --- | --- |
| Dose limiting 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 14 days after the first dose | 
| Maximum tolerated dose (MTD) or Maximum 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 14 days after the first dose | 
| Adverse Events during Treatment (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 | 
| Recommended dose for Phase II clinical studies (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 14 days after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| disease control rate (DCR) | Number of patients showing Complete Response (CR) or Partial Response (PR) based on RECIST for the best response. Number of patients showing Complete Response (CR, disappearance of all target lesions) or Partial Response (PR, at least a 30% decrease in the sum of longest diameter of target lesions taking as reference the baseline sum longest diameter) based on RECIST Criteria Version 1.0 (assessed by CT and/or MRI) for the best response. | Up to approximately 24 months | 
| 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 | 
| 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 | 
| Cmax | Maximum serum concentration (Cmax) of GNC-038 will be investigated. | Up to approximately 24 months | 
| Tmax | Time to maximum serum concentration (Tmax) of GNC-038 will be investigated. | Up to approximately 24 months | 
| AUC0-INF | Blood concentration - Area under time line. | Up to approximately 24 months | 
| AUC0-T | Blood concentration - Area under time line. | Up to approximately 24 months | 
| T1/2 | Blood concentration - Area under time line. | Up to approximately 24 months | 
| anti-drug antibody (ADA) in Ⅰa | Frequency and titer of anti-GNC-038 antibody (ADA). | Up to approximately 24 months | 
| DOR (Duration of Response) | 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 |