A Study of GNC-035 in Relapsed or Refractory Non-Hodgkin 's Lymphoma and Other Hematological Malignancies

An Open, Multicenter, Phase I / II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics / Pharmacodynamics and Antitumor Activity of GNC-035 Tetra-specific Antibody Injection in Relapsed or Refractory Non-Hodgkin 's Lymphoma and Other Hematological Malignancies

Phase I main objectives: To observe the safety and preliminary efficacy of GNC-035 in patients with relapsed/refractory non-Hodgkin lymphoma and other hematological malignancies, to determine the DLT and MTD, or MAD, and to determine RP2D. Phase II Main objective: To explore the efficacy of GNC-035 in patients with relapsed/refractory non-Hodgkin lymphoma and other hematological malignancies.

Study Overview

• Status: Recruiting
• Conditions: Non-hodgkin's Lymphoma
• Intervention / Treatment: Drug: GNC-035

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Hai Zhu, PHD; Phone Number: +8613980051002; Email: zhuhai@baili-pharm.com
• Study Contact Backup: Name: Sa Xiao, PHD; Phone Number: +8615013238943; Email: xiaosa@baili-pharm.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Recruiting
      • Beijing Cancer Hospital
      • Contact: Jun Zhu, PHD; Phone Number: 88196115; Email: zhujun3346@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects can understand the informed consent form, voluntarily participate in and sign the informed consent form.
2. No gender limit.
3. Age: ≥18 years old and ≤75 years old.
4. Expected survival time ≥3 months.
5. Histologically or cytologically confirmed relapsed/refractory non-Hodgkin lymphoma.

6. For patients with relapsed/refractory non-Hodgkin lymphoma. These include:

   Patients who experience failure of at least one line of standard therapy. Patients with relapsed or refractory disease who were not or not suitable for other therapies as judged by the investigator.

   Relapsed and refractory were defined as follows:

   Relapse was defined as disease progression after 6 months of response to adequate treatment with at least one anti-CD20 monoclonal antibody.

   Refractory was defined as refractory to anti-CD20 monoclonal antibody, failure to achieve remission after adequate treatment with anti-CD20 monoclonal antibody (combined chemotherapy or single agent), or disease progression during treatment or 6 months after completion of adequate treatment.

   Among them, "anti-CD20 monoclonal antibody regimen adequate treatment" refers to the completion of the full cycle of anti-CD20 monoclonal antibody combined with chemotherapy according to the pathological type and disease stage, such as rituximab monotherapy at a dose of 375 mg/m2 per week for at least 4 injections. Progression during treatment required the completion of at least one cycle of anti-CD20 monoclonal antibody combined with chemotherapy or monotherapy if progression occurred during induction therapy. At least one dose was completed if progression occurred during maintenance therapy. "Response" included complete and partial responses.

7. For non-Hodgkin lymphoma, at least one lesion must be evaluable during the uphill phase; The extension stage had to have at least one measurable lesion according to the Lugano criteria (lymph node lesion ≥1.5cm or extranodal lesion > 1.0cm).
8. ECOG ≤2.
9. Toxicity of previous antineoplastic therapy has returned to grade 1 or less as defined by NCI-CTCAE v5.0 (except for those indicators considered by the investigator to be possibly related to the disease, such as anemia, and those judged by the investigator to have no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stable with hormone replacement therapy).

10. Organ function within 7 days before the first dose:

    Bone marrow function: without blood transfusion, G-CSF (for 2 weeks), and medication correction within 7 days prior to screening Absolute neutrophil count (ANC) ≥1.0×109/L (≥0.5×109/L if the subject has bone marrow infiltration); Hemoglobin ≥80 g/L (≥70g/L if the subject has bone marrow infiltration); Platelet count ≥75×109/L; Liver function: total bilirubin, ≤1.5 ULN (Gilbert's syndrome, ≤3 ULN), and aminotransferase (AST/ALT), ≤2.5 ULN (for those with liver tumor invasive changes, ≤5.0 ULN) without correction with hepatoprotective medication within 7 days before screening examination Renal function: creatinine (Cr) ≤1.5 ULN and creatinine clearance (Ccr) ≥50 mL/ minute (according to Cockcroft and Gault formula) Urinalysis / 24-hour urine protein quantification: qualitative urine protein ≤1+ (if qualitative urine protein ≥2+, 24-hour urine protein < 1g is eligible) Cardiac function: left ventricular ejection fraction ≥50% Coagulation: fibrinogen ≥1.5g/L Activated partial thromboplastin time (APTT) ≤1.5×ULN; Prothrombin time (PT) ≤1.5×ULN.

11. Female subjects of childbearing potential or male subjects with a fertile partner must use highly effective contraception from 7 days before the first dose until 12 weeks after the last dose. Female subjects of childbearing potential must have a negative serum/urine pregnancy test within 7 days before the first dose.
12. Participants were able and willing to comply with protocol-specified visits, treatment plans, laboratory tests, and other study-related procedures.

Exclusion Criteria:

1. Patients who underwent major surgery within 28 days before study administration or who were scheduled to undergo major surgery during the study (" major surgery "was defined by the investigator).
2. Pulmonary disease grade ≥3 according to NCI-CTCAE v5.0, including dyspnea at rest or requiring continuous oxygen therapy; Patients with current interstitial lung disease (ILD) (except those who have recovered from previous interstitial pneumonia).
3. Active infections requiring systemic therapy, such as severe pneumonia, bacteremia, sepsis, etc.
4. patients with active autoimmune diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory intestinal diseases and Hashimoto's thyroiditis, etc., excluding type I diabetes mellitus, hypothyroidism that can be controlled only by replacement therapy, skin diseases without systemic treatment (such as vitiligo, psoriasis), etc.
5. Patients with other malignant tumors within 5 years before the first administration, cured non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ, gastrointestinal mucosal cancer, breast cancer, localized prostate cancer, and other patients without recurrence within 5 years were excluded.
6. Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBsAg positive or HBcAb positive and HBV-DNA test ≥ central detection lower limit) or hepatitis C virus infection (HCV antibody positive and HCV-RNA≥ central detection lower limit).
7. Hypertension poorly controlled by medication (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg).

8. A history of severe cardiovascular and cerebrovascular disease, including but not limited to:

   Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, grade III atrioventricular block, etc.

   Prolonged QT interval at rest (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 cardio-cerebrovascular event occurring within 6 months before the first dose.

   New York Heart Association (NYHA) class ≥II HF.

9. Patients with a history of allergy to recombinant humanized antibodies or to any of the excipients of GNC-035.
10. Women who are pregnant or breastfeeding.
11. Patients with central nervous system involvement.
12. Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (ALLo-HSCT).
13. Autologous hematopoietic stem cell transplantation (Auto-HSCT) within 12 weeks before starting GNC-035 therapy.
14. Current use of immunosuppressive agents, including, but not limited to, cyclosporine, tacrolimus, etc., within 2 weeks or 5 half-life periods prior to GNC-035 treatment, whichever is shorter.
15. Received radiotherapy, macromolecular targeted drugs within 4 weeks before GNC-035 treatment; Chemotherapy and a small-molecule targeted agent were administered 2 weeks or within five half-lives before treatment, whichever was less.
16. Have received anti-CD20 or anti-CD79b therapy within 4 weeks before starting GNC-035 and are responding.
17. Received CAR-T therapy within 12 weeks before GNC-035 treatment.
18. Use of a study drug from another clinical trial within 4 weeks or 5 half-lives, whichever was shorter, before the trial dose.
19. Other circumstances that the investigator deemed inappropriate for participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study treatment; Participants receive GNC-035 as intravenous infusion for the first cycle (3 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-035; GNC-035 was administered by intravenous infusion for 2 h-4 h, once a week ( IV, QW ), 3 weeks as a cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Phase I: Dose limiting toxicity (DLT)	DLTs are assessed according to NCI-CTCAE v5.0 during the first cycle and defined as occurrence of any of the toxicities in DLT definition if judged by the investigator to be possibly, probably or definitely related to study drug administration.	Up to 21 days after the first dose
Phase I: Maximum tolerated dose (MTD)	MTD is defined as the highest dose level at which no more than 1 in 6 participants experienced a DLT during the first cycle .	Up to 21 days after the first dose
Phase I: 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-035. The type, frequency and severity of TEAE will be evaluated during the treatment of GNC-035.	Up to approximately 24 months
Phase I: 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-035.	Up to 21 days after the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Progression-free survival (PFS)	The PFS is defined as the time from the participant's first dose of GNC-035 to the first date of either disease progression or death, whichever occurs first.	Up to approximately 24 months
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-035. The type, frequency and severity of TEAE will be evaluated during the treatment of GNC-035.	Up to approximately 24 months
Phase Ib: T1/2	Half-life (T1/2) of GNC-035 will be investigated.	Up to 21 days after the first dose
Phase I: 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 I: Complete Response (CR)	Complete response (CR) is defined as all tumor target lesions disappeared, no new lesions appeared, and tumor markers were normal for at least 4 weeks.	Up to approximately 24 months
Phase I: Cmax	Maximum Drug Concentration (Cmax) of GNC-035 will be investigated.	Up to 21 days after the first dose
Phase I: Tmax	Time at Which the Maximum (Tmax) of GNC-035 will be investigated.	Up to 21 days after the first dose
Phase I: AUC0-inf	Area Under the Curve（0-inf）of GNC-035 will be investigated.	Up to 21 days after the first dose
Phase I: AUC0-T	Area Under the Curve（0-t）of GNC-035 will be investigated.	Up to 21 days after the first dose
Phase I: CL	Rate of clearance of GNC-035 will be investigated.	Up to 21 days after the first dose
Phase I: Anti-drug antibody (ADA)	Frequency of anti-GNC-035 antibody (ADA) will be investigated.	Up to approximately 24 months

Collaborators and Investigators

• Sponsor: Sichuan Baili Pharmaceutical Co., Ltd.
• Collaborators: Baili-Bio (Chengdu) Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Jun Zhu, PhD, Peking University Cancer Hospital & Institute

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2023
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: September 27, 2023
• First Submitted That Met QC Criteria: September 27, 2023
• First Posted (Actual): October 4, 2023

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Hematological malignancies
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Hematologic Diseases; Neoplasms; Lymphoma; Hematologic Neoplasms
• Other Study ID Numbers: GNC-035-104

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No