Clinical trial NCT05485753: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Primary Central Nervous System Lymphoma
Secondary Central Nervous System Lymphoma
Lead sponsor: Sichuan Baili Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: SystImmune Inc.
name: Baili-Bio (Chengdu) Pharmaceutical Co., Ltd.
First posted: 2022-08-03
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Dose limiting toxicity (DLT)
timeFrame: Up to 17 days after the first dose
measure: Maximum tolerated dose (MTD) or maximum administrated dose (MAD)
timeFrame: Up to 17 days after the first dose
measure: Treatment-Emergent Adverse Event (TEAE)
timeFrame: Up to approximately 36 months
measure: The recommended dose for phase II clinical study（RP2D）
timeFrame: Up to 17 days after the first dose
Secondary outcomes:
measure: ORR (Objective Response Rate )
timeFrame: Up to approximately 36 months
measure: PFS (Progression-free Survival)
timeFrame: Up to approximately 36 months
measure: DCR (Disease Control Rate)
timeFrame: Up to approximately 36 months
measure: DOR (Duration of Response)
timeFrame: Up to approximately 36 months
measure: CR (Complete Response)
timeFrame: Up to approximately 36 months
measure: Adverse Events of special interest (AESI)
timeFrame: Up to approximately 36 months
measure: Peak Plasma Concentration（Cmax)
timeFrame: Up to 17 days after the first dose
measure: Incidence and titer of ADA (Anti-drug antibody)
timeFrame: :Up to approximately 36 months
measure: Incidence and titer of Nab
timeFrame: Up to approximately 36months
measure: Time to reach maximum concentration (Tmax)
timeFrame: Up to 17 days after the first dose
measure: AUC0-inf
timeFrame: Up to 17 days after the first dose
measure: AUC0-t
timeFrame: Up to 14 days after the first dose of GNC-038
measure: Plasma clearance （CL）
timeFrame: Up to 17 days after the first dose
measure: Elimination half life （T1/2）
timeFrame: Up to 17 days after the first dose
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital, Capital Medical University
state: Beijing
city: Beijing
country: China
facility: Beijing GoBroad Boren Hospital
state: Beijing
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
state: Guangdong
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
Study officials:
affiliation: Beijing Tiantan Hospital
name: Wenbin Li
role: PRINCIPAL_INVESTIGATOR
References: