Clinical trial NCT05623982: Phase Ib/II Study of GNC-038 Injection in Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non-hodgkin's Lymphoma
Lead sponsor: Sichuan Baili Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: SystImmune Inc.
name: Baili-Bio (Chengdu) Pharmaceutical Co., Ltd.
First posted: 2022-11-21
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: 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.

Primary outcomes:
measure: Dose limiting toxicity (DLT)
timeFrame: Up to 14 days after the first dose
measure: Maximum tolerated dose (MTD) or Maximum dose (MAD)
timeFrame: Up to 14 days after the first dose
measure: Adverse Events during Treatment (TEAE)
timeFrame: Up to approximately 24 months
measure: Recommended dose for Phase II clinical studies (RP2D)
timeFrame: Up to 14 days after the first dose
Secondary outcomes:
measure: disease control rate (DCR)
timeFrame: Up to approximately 24 months
measure: progression-free survival (PFS)
timeFrame: Up to approximately 24 months
measure: Adverse Events of Special Interest (AESI)
timeFrame: Up to approximately 24 months
measure: Cmax
timeFrame: Up to approximately 24 months
measure: Tmax
timeFrame: Up to approximately 24 months
measure: AUC0-INF
timeFrame: Up to approximately 24 months
measure: AUC0-T
timeFrame: Up to approximately 24 months
measure: T1/2
timeFrame: Up to approximately 24 months
measure: anti-drug antibody (ADA) in Ⅰa
timeFrame: Up to approximately 24 months
measure: DOR (Duration of Response)
timeFrame: Up to approximately 24 months
Other outcomes:
measure: Neutralizing antibody (Nab) in phase Ⅰb
timeFrame: Up to approximately 24 months
measure: Overall survival (OS) in phaseⅠb and phase Ⅱ
timeFrame: Up to approximately 24 months
measure: Neutralizing antibody (Nab) in phaseⅡ
timeFrame: Up to approximately 24 months
measure: anti-drug antibody (ADA) in phaseⅡ
timeFrame: Up to approximately 24 months
Locations:
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Haerbin
country: China
facility: Harbin First Hospital
state: Heilongjing
city: Qingdao
country: China
facility: Qingdao Central Hospital
state: Shandong
Study officials:
affiliation: Peking University Cancer Hospital & Institute
name: Jun Zhu
role: PRINCIPAL_INVESTIGATOR
affiliation: Peking University Cancer Hospital & Institute
name: Yuqin Song
role: PRINCIPAL_INVESTIGATOR
References: