A Study of GNC-038, a Tetra-specific Antibody, in Participants With R/R Diffuse Large B-cell Lymphoma (DLBCL)

• ClinicalTrials.gov Identifier: NCT05192486
• Recruitment Status: Recruiting
• First Posted: January 14, 2022
• Last Update Posted: April 4, 2024
• Sponsor: Sichuan Baili Pharmaceutical Co., Ltd.
• Collaborator: SystImmune Inc.
• Information provided by (Responsible Party): Sichuan Baili Pharmaceutical Co., Ltd.

Study Description

Brief Summary:

In this study, the safety and preliminary efficacy of GNC-038 in participants with recurrent or refractory Diffuse Large B-cell lymphoma (DLBCL) 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.

Condition or disease	Intervention/treatment	Phase
Diffuse Large B-cell Lymphoma	Drug: GNC-038	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center, Phase Ib/II Study to Evaluate the Safety, Tolerability and Pharmacokinetic Characteristics of Tetra-specific Antibody GNC-038 in Participants With Recurrent or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
• Actual Study Start Date: August 10, 2022
• Estimated Primary Completion Date: August 2024
• Estimated Study Completion Date: August 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Study treatment; Participants receive GNC-038 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-038; Administration by intravenous infusion

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicity (DLT) [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
   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).
2. Maximum tolerated dose (MTD) or maximum administrated dose (MAD) [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
   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.
3. Treatment-Emergent Adverse Event (TEAE) [ Time Frame: Up to approximately 24 months ]
   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.
4. The recommended dose for phase II clinical study（RP2D） [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
   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.

Secondary Outcome Measures :

1. ORR (Objective Response Rate ) [ Time Frame: Up to approximately 24 months ]
   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.
2. PFS (Progression-free Survival) [ Time Frame: Up to approximately 24 months ]
   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.
3. DCR (Disease Control Rate) [ Time Frame: Up to approximately 24 months ]
   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]).
4. DOR (Duration of Response) [ Time Frame: Up to approximately 24 months ]
   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.
5. CR (Complete Response) [ Time Frame: Up to approximately 24 months ]
   Disappearance of all target lesions.
6. Adverse Events of special interest (AESI) [ Time Frame: Up to approximately 24 months ]
   AESI is an event of scientific and medical interest specific to the sponsor's product or research project.
7. Peak Plasma Concentration（Cmax) [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
   Maximum serum concentration (Cmax) of GNC-038 will be investigated.
8. Incidence and titer of ADA (Anti-drug antibody) [ Time Frame: Up to approximately 24 months ]
   Frequency and titer of anti-GNC-038 antibody (ADA) will be evaluated.
9. Incidence and titer of Nab [ Time Frame: Up to approximately 24 months ]
   Incidence and titer of Nab of GNC-038 will be evaluated.
10. Trough steady-state concentration（Css） [ Time Frame: Up to 14 days after the first dose of GNC-038 ]
    Concentration of GNC-038 at steady state plateau will be investigated.
11. Time to reach maximum concentration (Tmax) [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
    Time to maximum serum concentration (Tmax) of GNC-038 will be investigated.
12. AUC0-inf [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
    Area under the plasma concentration-time curve from time 0 extrapolated to infinite (AUC0-inf).
13. AUC0-t [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
    Area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC0-t).
14. Plasma clearance （CL） [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
    To study the serum clearance rate of GNC-038 per unit time.
15. Elimination half life （T1/2） [ Time Frame: Up to 21 days after the first dose of GNC-038 ]
    Half-life (T1/2) of GNC-038 will be investigated.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. he participants could understand and sign the informed consent form, and must participate voluntarily;
2. No gender limit;
3. Age: ≥18 years old and ≤75 years;
4. Expected survival time ≥ 3 months;
5. Has suffered from Diffuse Large B-cell lymphoma (DLBCL) confirmed by histology or cytology;

6. a. Those who have recurrent or refractory Diffuse Large B-cell lymphoma (DLBCL).

   b. Recurrent or refractory participants that are, determined by the investigators, not applicable/tolerated to other treatments.

   Recurrent and refractory are defined as follows:

   Recurrent is the progression of disease after adequate treatment to remission, with at least one regimen containing rituximab.

   Refractory refers to failure to respond to adequate treatment with rituximab containing regimen (combination chemotherapy or monotherapy) or disease progression during treatment/within 6 months of completion of adequate treatment.

   "Adequate treatment with rituximab regimen" refers to the completion of rituximab combined with chemotherapy based on pathological type and disease stage requirements, or rituximab monotherapy with 375 mg/m2 injections at least 4 times a week. "Progress during treatment" requires completion of at least one cycle of rituximab plus chemotherapy or monotherapy if progress during induction therapy; At least one injection is completed if progress is made during maintenance therapy. "Mitigation" includes complete and partial mitigation.

7. There are measurable lesions during the screening period (any long diameter of lymph node lesions ≥ 1.5 cm or any long diameter of extra-nodal lesions greater than 1.0 cm);
8. Physical fitness score ECOG≤2；
9. The toxicity of the previous anti-tumor therapy has been restored to the level ≤1 defined by NCI-CTCAE v5.0 (the investigators considered indicators that might be associated with the disease, such as anemia, and excluded toxicities that the investigators considered to be of no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stabilized by hormone replacement therapy);

10. The organ function within 7 days prior to the first administration meets the following requirements:

    • Bone marrow function: In the case of no blood transfusion, no use of G-CSF (no use of long-acting whitening needles within 2 weeks) and drug correction within 7 days prior to screening, the absolute value of neutrophil count (ANC) ≥1.0×109/L (participants with bone marrow infiltration ≥0.5×109/L); Hemoglobin ≥80 g/L (for participants with bone marrow infiltration, ≥70 g/L); Platelet count ≥50×109/L;
    • Liver function: In the absence of hepatoprotective drugs for correction within 7 days prior to screening, total bilirubin (TBIL) ≤ 1.5 ULN (TBIL ≤3 ULN in participants with Gilbert's syndrome), transaminase (AST/ALT) ≤ 2.5 ULN (participants with tumor infiltration in the liver ≤5.0 ULN);
    • Kidney function: creatinine (Cr) ≤ 1.5 ULN and creatinine clearance (Ccr) ≥ 50 mL/min (according to the Cockcroft and Gault formula);
    • Routine urine / 24h urine protein quantification: qualitative urine protein ≤1+ (if qualitative urine protein ≥2+, 24h urine protein < 1g can be included);
    • Cardiac function: left ventricular ejection fraction ≥50%;
    • Coagulation function: fibrinogen (FIB) ≥1.5g/L; activated partial thromboplastin time (APTT) ≤1.5×ULN; prothrombin time (PT) ≤1.5×ULN.
11. Female participants with fertility or male participants whose partner(s) are fertile must take effective contraceptive measures from 7 days prior to the first administration to 24 weeks after the administration. Female participants with fertility must have a negative serum/urine pregnancy test in 7 days prior to the first dose.
12. The subjects are able and willing to follow the visits, treatment plans, laboratory tests, and other study-related procedures specified in the study protocol.

Exclusion Criteria:

1. Has grade 3 or above lung disease defined 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. Participants at risk of 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 (such as vitiligo, psoriasis), B cells caused by autoimmune disease;
5. Complicated with other malignant tumors within 5 years prior to GNC-038 treatment, except for non-melanoma skin cancer in situ, superficial bladder cancer, cervical cancer in situ, gastrointestinal intramucosal cancer, breast cancer and localized prostate cancer that have been cured and have not recurred within 5 years;
6. HBsAg or HBcAb positive and HBV-DNA test ≥ULN; HCV antibody positive and HCV-RNA≥ULN; HIV antibody positive;
7. Participants with poorly controlled hypertension by antihypertensive drugs (systolic blood pressure>150 mmHg or diastolic blood pressure>100 mmHg);

8. History of severe heart disease, including but not limited to:

   • There are serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias, III grade atrioventricular block, which require clinical intervention;
   • Participants with prolonged QT interval (male QTc > 450 msec or female QTc > 470 msec);
   • Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or above cardiovascular and cerebrovascular events occurred within 6 months before the first administration;
   • New York Heart Association (NYHA) grade II, III or IV congestive heart failure;
9. Patients with a history of allergy to recombinant humanized antibodies or to any excipient component of GNC-038;
10. Pregnant or breastfeeding women;
11. There is an invasion of the central nervous system;
12. Has undergone major surgery within 28 days prior to the administration of this study, or planned to undergo major surgery during the study period (except for surgery such as puncture or lymph node biopsy);
13. Has accepted organ transplantation or allogeneic hematopoietic stem cell transplantation (ALLo-HSCT);
14. Has accepted autologous hematopoietic stem cell transplantation (Auto-HSCT) within 12 weeks prior to GNC-038 treatment;
15. Currently using immunosuppressive agents within 2 weeks prior to GNC-038 treatment, including but not limited to: Cyclosporine, tacrolimus, etc.; receiving high-dose glucocorticoids within 2 weeks prior to GNC-038 treatment (longer than 14 days, a stable dose of >30 mg of prednisone or other glucocorticoids at the same dose per day);
16. Has received radiotherapy within 4 weeks prior to GNC-038 treatment;
17. Has received anti-CD20 or anti-CD79b treatment within 4 weeks prior to GNC-038 treatment, and continued to respond;
18. Has received chemotherapy, small molecule targeted drugs within 2 weeks prior to GNC-038 treatment;
19. Has received CAR-T treatment within 12 weeks prior to GNC-038 treatment.
20. Has participated in any other clinical trials within 4 weeks prior to GNC-038 treatment;
21. Other conditions that the investigator believes that it is not suitable for participating in this clinical trial.

Contacts and Locations

Contacts

Contact: Hai Zhu; +86-13980051002; zhuhai@baili-pharm.com

Contact: Sa Xiao; +86-15013238943; xiaosa@baili-pharm.com

Locations

China, Guangdong

Shenzhen Second People's Hospital; Recruiting

Shenzhen, Guangdong, China

Contact: Xin Du

China, Hebei

Affiliated Hospital of Hebei University; Recruiting

Baoding, Hebei, China

Contact: Aiming Zang

China, Henan

The First Affiliated Hospital of Henan University of Science and Technology; Recruiting

Luoyang, Henan, China

Contact: Haiping Yang

China, Shanghai

Ruijin Hospital, Shanghai JiaoTong University School of Medicine; Recruiting

Shanghai, Shanghai, China, 200025

Contact: Weili Zhao 13621999905 zwl_trial@163.com

Principal Investigator: Weili Zhao

Sponsors and Collaborators

Sichuan Baili Pharmaceutical Co., Ltd.

SystImmune Inc.

Investigators

• Principal Investigator: Weili Zhao; Ruijin Hospital

More Information

• Responsible Party: Sichuan Baili Pharmaceutical Co., Ltd.
• ClinicalTrials.gov Identifier: NCT05192486
• Other Study ID Numbers: GNC-038-102
• First Posted: January 14, 2022
• Last Update Posted: April 4, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sichuan Baili Pharmaceutical Co., Ltd.:

DLBCL

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin