A Study of GNC-038, a Tetra-specific Antibody, in Patients With Central Nervous System Lymphoma (PCNSL) and Relapsed or Refractory Secondary Central Nervous System Lymphoma (SCNSL)

Study Overview
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Brief Summary
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In this study, the safety and preliminary efficacy of GNC-038 in patients with r relapsed or refractory primary central nervous system lymphoma (PCNSL) and relapsed or refractory secondary central nervous system lymphoma (SCNSL) 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.

Official Title
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An Open, Multicenter, Phase Ib/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics/Pharmacodynamics, and Antitumor Activity of Tetra-specific Antibody GNC-038 Injection in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma (PCNSL) and Relapsed or Refractory Secondary Central Nervous System Lymphoma (SCNSL)

Conditions
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Primary Central Nervous System Lymphoma, Secondary Central Nervous System 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, participate in and sign the informed consent voluntarily; 2. No gender limitation; 3. Age: ≥18; 4. Expected survival time ≥3 months; 5. Patients with primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) confirmed by histology or cytology; 6. A. Patients with recurrent/refractory primary central nervous system lymphoma (PCNSL) and recurrent/refractory secondary central nervous system lymphoma (SCNSL) may be associated with ocular lymphoma;B. Patients with relapsed or refractory primary CNS lymphoma (PCNSL) and relapsed or refractory secondary CNS lymphoma (SCNSL) who were not eligible or intolerant to other therapies were determined by the investigator;Recurrence and refractory are defined as follows: Recurrence refers to the emergence of new lesions after adequate treatment to complete response (CR).Refractory refers to a patient who has experienced at least first-line treatment without disease remission, e.g. induction chemotherapy with methotrexate without CR. 7. KPS score ≥60; 8. Adverse reactions of previous antitumor therapy returned to CTCAE 5.0 grade ≤1 (except for the indicators that the researchers considered to be related to the disease, such as anemia, and toxicities that the researchers determined to be without safety risk, such as alopecia, grade 2 peripheral neurotoxicity, hypothyroidism stabilized by hormone replacement therapy, etc.); 9. Before the first administration, the organ function level should meet the following requirements: Bone marrow function: In the absence of blood transfusion, G-CSF (long-acting white needle within 2 weeks) and medication correction within 7 days prior to screening: Absolute neutrophil count (ANC) ≥15×10^9/L (subjects with bone marrow infiltration should be ≥0.5×10^9/L);Hemoglobin ≥90 g/L;Platelet count ≥90×10^9/L; Liver function: Total bilirubin ≤1.5 ULN (Gilbert's syndrome ≤3 ULN), transaminase (AST/ALT) ≤2.5 ULN (≤5.0 ULN for subjects with tumor invasive changes in the liver) without correction with hepatoprotective drugs within 7 days prior to screening; Renal function: Creatinine (Cr) ≤1.5 ULN and creatinine clearance (Ccr) ≥50 mL /min according to the Cockcroft and Gault formula; Routine urine / 24-hour urine protein quantification: qualitative urine protein ≤1+ (if qualitative urine protein ≥2+, 24-hour urine protein < 1g can be included); 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. 10. Fertile female subjects or male subjects with fertile partners must use highly effective contraception beginning 7 days before the first dose and up to 12 weeks after the last dose. Fertile female subjects must have a negative serum/urine pregnancy test within 7 days prior to initial dosing; 11. The subject is able and willing to follow the visits, treatment plans, laboratory tests, and other study-related procedures specified in the study protocol. Exclusion Criteria: 1. Lung disease defined as grade ≥3 according to 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 tuberculosis; 4. Brain stem tumor infiltration or only eye lesions; 5. 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; 6. Non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer, localized prostate cancer and other cancers that have been cured and have not recurred within 5 years prior to the first administration are excluded; 7. HBsAg positive or HBcAb positive, and HBV-DNA test ≥ the upper limit of normal; HCV antibody positive and HCV-RNA≥ the upper limit of normal value; HIV antibody positive; 8. Poorly controlled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg); 9. Have a history of serious cardiovascular and cerebrovascular diseases, including but not limited to: Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias and degree ⅲ ATrioventricular block requiring clinical intervention; Longer QT interval at rest (QTc > 450 msec for men or 470 msec for women); Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months prior to first administration; Heart failure with the New York Heart Association (NYHA) Heart function rating ≥II; 10. Patients with a history of allergy to recombinant humanized antibodies or to any excipient ingredient of GNC-038; 11. Pregnant or breastfeeding women; 12. Patients who cannot tolerate MRI examination; 13. Patients who underwent major surgery within 28 days prior to administration of the drug in this study, or who planned to undergo major surgery during the study period (except for puncture or biopsy surgery); 14. Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (ALLO-HSCT); 15. Autologous hematopoietic stem cell transplantation (AUTO-HSCT) within 12 weeks prior to initiation of GNC-038 therapy; 16. Immunosuppressants are being used, including but not limited to: Cyclosporine, tacrolimus, etc. within 2 weeks prior to gnC-038 treatment; Gnc-038 received a high dose of glucocorticoid for 2 weeks prior to treatment (longer than 14 days, a steady dose of dexamethasone >5mg per day or equivalent dose of other glucocorticoids); 17. Received radiotherapy within 4 weeks prior to initiation of GNC-038 treatment; 18. Received anti-CD20 or anti-CD79B treatment within 4 weeks prior to initiation of GNC-038 and still responded; 19. Received chemotherapy and small molecule targeted therapy within 2 weeks prior to treatment; 20. Received CAR-T therapy within 12 weeks prior to initiation of GNC-038; 21. Participated in any other clinical trials within 4 weeks prior to administration of this trial; 22. Past or present central nervous system disease, including, but not limited to, stroke (imaging) 23. Medical examination indicated lacunar cerebral infarction except those requiring no treatment), severe brain injury, Senile dementia, Parkinson's disease, organic brain syndrome, psychosis; 24. Other conditions that the investigator considers inappropriate for participation in this clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group 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 during treatment were graded according to the National Cancer Institute Standard for Common Terminology for Adverse Events (NCI-CTCAE, v5.0). | Up to 17 days after the first dose | 
| Maximum tolerated dose (MTD) or maximum administrated 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 17 days after the first dose | 
| 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 36 months | 
| The recommended dose for phase II clinical study（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 17 days after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR (Objective Response Rate ) | 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 36 months | 
| PFS (Progression-free Survival) | 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 36 months | 
| DCR (Disease Control Rate) | 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 36 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 36 months | 
| CR (Complete Response) | Disappearance of all target lesions. | Up to approximately 36 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 36 months | 
| Peak Plasma Concentration（Cmax) | Maximum serum concentration (Cmax) of GNC-038 will be investigated. | Up to 17 days after the first dose | 
| Incidence and titer of ADA (Anti-drug antibody) | Frequency and titer of anti-GNC-038 antibody (ADA) will be evaluated. | :Up to approximately 36 months | 
| Incidence and titer of Nab | Incidence and titer of Nab of GNC-038 will be evaluated. | Up to approximately 36months | 
| Time to reach maximum concentration (Tmax) | Time to maximum serum concentration (Tmax) of GNC-038 will be investigated. | Up to 17 days after the first dose | 
| AUC0-inf | Area under the plasma concentration-time curve from time 0 extrapolated to infinite (AUC0-inf). | Up to 17 days after the first dose | 
| AUC0-t | Area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t). | Up to 14 days after the first dose of GNC-038 | 
| Plasma clearance （CL） | To study the serum clearance rate of GNC-038 per unit time. | Up to 17 days after the first dose | 
| Elimination half life （T1/2） | Blood concentration - Area under time line. | Up to 17 days after the first dose |