Clinical Trial of TQB2825 Injection Combined Immunochemotherapy in Subjects With Diffuse Large B Cell Lymphoma

Phase Ib/II Clinical Trial of TQB2825 Injection Combined Immunochemotherapy in Subjects With Diffuse Large B Cell Lymphoma

To explore the efficacy and safety of TQB2825 injection combined immunochemotherapy in subjects with untreated or R/R DLBCL.

The efficacy evaluation indicators are objective response rate (ORR), complete response rate (CR rate),progression free survival (PFS), duration of response (DOR) and overall survival(OS).

The safety evaluation indicators are dose-limiting toxicity (DLT) , maximum tolerated dose (MTD)and recommended phase II dose (RP2D).

Inclusion Criteria:

• Subjects voluntarily participate in this study, sign the informed consent form, and have good compliance;

• Age 18 to under 80 years old (calculated from the date of signing the informed consent form);

• Eastern Cooperative Oncology Group (ECOG) score of 0 to 2;

• Life expectancy greater than 12 weeks;

• In the dose expansion phase, previously untreated patients with International Prognostic Index (IPI) scores of 2-5;

• A confirmed diagnosis of diffuse large B-cell lymphoma or grade 3b follicular lymphoma, in accordance with the 2022 World Health Organization (WHO) diagnostic criteria, based on histology or cytology (including diffuse large B-cell lymphoma-not otherwise specified and transformed from indolent lymphomas, not allowing for the following types or components: double-hit, triple-hit, or high-grade B-cell lymphoma-not otherwise specified, mediastinal large B-cell lymphoma, T/histiocyte-rich large B-cell lymphoma, human herpesvirus 8 (HHV8)-positive/primary effusion lymphoma, Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma, Burkitt's lymphoma, and Hodgkin's lymphoma, etc.);

• Immunophenotypic analysis shows that the tumor is CD20 positive;

• Previous treatment meets the following criteria:

  1. Combined with R-CHOP patients: previously untreated diffuse large B-cell lymphoma patients, allowing for corticosteroid pre-treatment (with or without vincristine) or non-curative palliative local radiotherapy.
  2. Combined with GemOx patients: patients with diffuse large B-cell lymphoma who have received at least one line of systemic treatment (including at least one line with CD20 monoclonal antibody) and are not suitable for hematopoietic stem cell transplantation or have failed treatment after transplantation or relapsed, and whose disease progressed during the most recent treatment or relapsed after completion of treatment or confirmed no objective response after adequate treatment.

• According to the 2014 Lugano criteria, there is at least one measurable lesion, i.e., lymph node lesions with a long diameter >15 mm or extranodal lesions with a long diameter >10 mm based on CT cross-sectional imaging; Positron emission tomography (PET)-computed tomography (CT) scan shows PET positivity;

• Laboratory tests meet the following criteria (not corrected with blood transfusion or hematopoietic growth factors within 14 days before screening):

  1. Hemoglobin (HGB) ≥80g/L;
  2. Absolute neutrophil count (NEUT) ≥1.0×10∧9/L;
  3. Platelet count (PLT) ≥ 75×10∧9/L (if accompanied by bone marrow invasion, platelets ≥50×10∧9/L).
  4. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);
  5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ULN. If accompanied by liver metastasis, then ALT and AST ≤ 5 ULN;
  6. Serum creatinine (CR) ≤ 1.5 ULN or estimated glomerular filtration rate ≥50 ml/min by the Cockcroft-Gault formula.
  7. Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5×ULN (not on anticoagulant therapy);

• Women of childbearing age must agree to use effective contraceptive measures during the study and for 12 months after the study ends, with a negative serum or urine pregnancy test within 7 days before study enrollment; men must agree to use effective contraceptive measures during the study and for 12 months after the study ends.

Exclusion Criteria:

• The subject has had or currently has other malignant tumors that occurred within 5 years before the first dose of the study drug. The following two situations are eligible for enrollment: other malignant tumors that have been treated with single surgery and have achieved continuous 5 years of disease-free survival (DFS); cured carcinoma in situ of the cervix, non-melanoma skin cancer, and superficial bladder tumors [Ta (non-invasive tumors), Tis (carcinoma in situ), and T1 (tumors infiltrating the basement membrane)];

• Adverse reactions from previous treatments have not recovered to a Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade score of ≤1, except for grade 2 alopecia, non-clinically significant and asymptomatic laboratory abnormalities, and hypothyroidism stabilized with hormone replacement therapy, which are deemed to have no safety risks by the investigator;

• Received major surgical treatment, significant traumatic injury within 4 weeks before the first dose, or expected to undergo major surgery during the study treatment period, or has long-term unhealed wounds or fractures;

• Any subject with bleeding or bleeding events ≥CTC AE grade 3 within 4 weeks before the first dose;

• A history of arterial/venous thrombotic events within 6 months before the first dose, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis, and pulmonary embolism, or any other history of serious thromboembolism (thrombosis from implanted venous access ports or catheters, or superficial vein thrombosis is not considered "serious" thromboembolism);

• Clinically significant uncontrollable pleural effusion requiring repeated drainage, ascites, moderate or greater pericardial effusion;

• Decompensated cirrhosis (Child-Pugh liver function rating of B or C) and active hepatitis (hepatitis B reference: positive HBsAg, and positive hepatitis B virus (HBV) DNA or detection value exceeding the lower limit of detection; hepatitis C reference: positive HCV antibody, and positive hepatitis C virus (HCV) RNA or detection value exceeding the lower limit of detection); Note: Subjects with hepatitis B who are positive for HBsAg, regardless of whether their HBV DNA is detectable, must continue antiviral treatment (nucleoside analogs recommended) and regularly monitor HBV DNA; for subjects with hepatitis B who are positive for HBcAb but negative for HBsAg, regular monitoring of HBV DNA is required, and prophylactic antiviral treatment is recommended; for hepatitis C subjects, regular monitoring of HCV RNA is required.

• Pulmonary diseases, including any of the following conditions:

  1. Past or present non-infectious pneumonia requiring treatment with corticosteroids (including but not limited to acute respiratory distress syndrome, acute hypersensitivity pneumonia, drug-related pneumonia, bronchospasm, acute interstitial pneumonia, idiopathic pulmonary interstitial fibrosis, etc.);
  2. Past or present chronic obstructive pulmonary disease (COPD), and forced expiratory volume in one second (FEV1) <60% (predicted value);

• Brain or mental abnormalities, including any of the following conditions:

  1. A history of substance abuse that cannot be quit;
  2. Accompanying or past central nervous system disease history, including epileptic seizures, hemorrhagic/ischemic stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, paralysis, aphasia, mental illness, consciousness disturbance, unexplained coma, neuropathy, organic brain syndrome, etc.;
  3. Brain MRI evidence indicating inflammatory lesions and/or vasculitis;
  4. Cerebrovascular accidents, cerebral infarction, etc., within 6 months before the first dose;

• Major cardiovascular diseases, including any of the following conditions:

  1. Heart failure of more than grade II according to the New York Heart Association (NYHA) standards or cardiac ultrasound examination: Left ventricular ejection fraction (LVEF) <50%;
  2. A history of clinically significant ventricular arrhythmias (such as sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes ventricular tachycardia) or arrhythmias requiring continuous antiarrhythmic drug treatment;
  3. A history of myocardial infarction, serious arrhythmias, unstable angina, etc., within 6 months before the first dose;
  4. The Fridericia-corrected QT interval (QTcF) is >450 milliseconds (msec) for males and >470 msec for females (if QTc is abnormal, it can be measured three times continuously with an interval of more than 2 minutes, and the average value can be taken);
  5. A history or family history of congenital long QT syndrome;
  6. Hypertension that cannot be controlled with a combination of two drugs (at least two measurement results are systolic pressure ≥160 mmHg, diastolic pressure ≥100 mmHg);

• Active or uncontrolled infections (≥CTC AE grade 2 infections), including bacterial, fungal, or viral infections (including but not limited to active pneumonia, syphilis, tuberculosis, and Coronavirus disease 2019 (COVID-19), etc. During the screening period, Polymerase chain reaction (PCR) testing or two antigen tests for COVID-19 must be performed (with an interval of at least 24 hours), and the test results must be negative to be eligible. Subjects who do not meet the COVID-19 infection eligibility criteria must fail the screening, and can only be re-screened under the following conditions: asymptomatic subjects at least 10 days after the first positive test result, or symptomatic subjects at least 10 days after the onset of symptoms);

• Renal failure requiring hemodialysis or peritoneal dialysis, history of nephrotic syndrome;

• A history of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases;

• Having or having had autoimmune diseases that require treatment, subjects receiving stable replacement therapy for hypothyroidism, and type 1 diabetes can be enrolled.

• Prepared for or having received organ transplantation, or having obvious host-graft reactions, or having received allogeneic hematopoietic stem cell transplantation in the past;

• Need for systemic immunosuppressive treatment, including but not limited to: use of cyclosporine, tacrolimus, etc., within 4 weeks before the first dose, receiving high-dose glucocorticoid therapy (prednisone >30 mg/day or equivalent dose of other glucocorticoids), or receiving any other immunosuppressive treatment. Subjects receiving inhaled or local corticosteroid treatment, or those who have been receiving a stable dose of prednisone <10 mg/day or equivalent dose of other glucocorticoids for systemic treatment for at least 4 weeks before the first dose, or those receiving prophylactic medication to prevent infusion reactions before the administration of the trial medication can be enrolled;

• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH);

• For relapsed/refractory patients, previous anti-tumor treatments:

  1. Received chemotherapy, immunotherapy, monoclonal antibody treatment within 4 weeks before the first dose, radiotherapy or small molecule targeted drugs within 2 weeks, or still within the 5 half-lives of the drug (the shortest appearing time shall prevail), the washout period is calculated from the end of the last treatment;
  2. Received traditional Chinese medicine (including Compound Eschar Capsules, Kangai Injection, Kanglaite Capsules/Injection, Aidi Injection, Yanzaizi Oil Injection/Capsules, Xiaocaiping Tablets/Injection, Huachansu Capsules, etc.) with anti-tumor indications approved by the National Medical Products Administration (NMPA) in the drug instructions within 2 weeks before the first dose;
  3. Previously used other antibody drugs targeting both CD3 and CD20;
  4. Received Chimeric antigen receptor T (CAR-T) treatment or other immune cell therapy, or autologous hematopoietic stem cell transplantation (auto-HSCT) within 3 months before the first dose;
  5. Previously received R-GemOx or GemOx treatment;

• Known allergies to excipient components of the study drug.

• Participated in and used other anti-tumor clinical trial drugs within 4 weeks or 5 half-lives before the first dose.

• In the judgment of the investigator, there are situations that seriously endanger the safety of the subject or affect the subject's completion of the study.