Camrelizumab in Combination With Apatinib in Refractory and Relapsed DLBCL

This study will evaluate the efficacy and safety of camrelizumab in combination with apatinib in in patients with relapsed or refractory diffuse large B cell lymphoma failed from second line chemotherapy.

Patients with relapsed /refractory diffuse large B cell lymphoma usually have a bad prognosis. These patients cannot be treated successfully with the conventional chemotherapy of CHOP. Apatinib is a new type of oral tyrosine kinase inhibitor targeting VEGFR-2. Some studies have shown that the combination of low-dose apatinib and camrelizumab shows a synergistic effect in the exploration of multiple solid tumors, and the adverse reactions of low-dose apatinib are significantly reduced, and the patients are well tolerated.The investigators will evaluate the efficacy and safety of camrelizumab in combination with apatinib in the patients with relapsed refractory diffuse large B cell lymphomafailed from second line chemotherapy.

Eligibility Criteria:
Inclusion Criteria:

1. Age range 18-80 years old; male or female
2. DLBCL, or follicular lymphoma grade 3B, or transformed DLBCL, EBV (+) DLBCL, ALK (+) DLBCL, high-grade lymphoma were confirmed by histopathology examination;
3. Failed from standard first-line rituximab-contained chemotherapy, and relapsed or refractory after second-line regimens with or without rituximab.
4. Estimated survival time \> 3 months.
5. There must be at least one evaluate able or measurable lesion that meets the LYRIC 2016 Malignant Lymphoma criteria \[evaluable lesion: 18F-fluorodeoxyglucose/Positron Emission Tomography (18FDG/PET) examination showing increased lymph node or extranodal uptake (higher than liver) and PET and/or computed tomography (Computed Tomography) CT) features are consistent with lymphoma findings; lesions can be measured: nodular lesions \> 15mm or extranodal lesions \> 10mm (if the only measurable lesion has received radiotherapy in the past, there must be evidence of radiological progress after radiotherapy), and accompanied by increased 18FDG uptake). Except for this, there is no measurable increase in diffuse 18FDG uptake in the liver;
6. ECOG performance status 0-2.
7. Prior chemotherapy and radiotherapy should have been completed more than 4 weeks.
8. Adequate organ and bone marrow function, no severe hematopoietic dysfunction, cardiac, pulmonary, liver, kidney, thyroid dysfunction and immune deficiency (no blood transfusion, granulocyte colony stimulating factor or other medical support was received within 14 days prior to the use of the research drug): 1) The absolute value of neutrophils (\>1.5×10\^9/L); 2) platelet count (\> 75×10\^9/L); 3) Hemoglobin (\> 9 g/dL); 4) Upper Limit Normal (ULN) or creatinine clearance rate (\>40 mL/min) of serum creatinine (\<1.5 times normal value upper limit) (estimated by Cockcroft-Gault formula); 5) Serum total bilirubin \< 1.5 times ULN; 6) Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) = 2.5 times ULN; 7) Coagulation function: International Normalized Ratio (INR) = 1.5 times ULN; Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) = 1.5 times ULN (unless the subject is receiving anticoagulant therapy and PT and APTT are using anticoagulant therapy at screening time). Within the expected range; 8) Thyrotropin (TSH) or free thyroxine (FT4) or free triiodothyronine (FT3) were all within the normal range (+10%);
9. There was no evidence that subjects had difficulty breathing at rest, and the measured value of pulse oximetry at rest was more than 92%;
10. Participants must pass a pulmonary function test (PFT) to confirm that forced expiratory volume (FEV1)/forced vital capacity (FVC) in the first second is more than 60%, unless it is a large mediastinal mass caused by lymphoma that cannot meet this standard; carbon monoxide diffusion (DLCO), FEV1 and FVC are all above 50% of the predicted value; all PFT results must be obtained within four weeks before the first administration;
11. Female patients of childbearing age must have a negative pregnancy test at the time of enrollment and are willing to use reliable contraceptive methods, i.e. barrier methods, oral contraceptives, implant methods, skin contraception, long-acting injection contraceptives, intrauterine devices, or tubal ligation;
12. Paraffin tissue specimens or fresh puncture tissue specimens are available;
13. Volunteers who signed informed consent.

Exclusion Criteria:

1. Primary central nervous system lymphoma or secondary central nervous system involvement;
2. Hemophagocytic syndrome;
3. Previously treated with immunological checkpoint inhibitors (PD-1, PD-L1, CTLA-4, etc.);
4. Previously treated with Apatinib.
5. Patients with active autoimmune diseases requiring systematic treatment in the past two years (hormone replacement therapy is not considered systematic treatment, such as type I diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy, adrenocortical dysfunction or pituitary dysfunction requiring only physiological doses of glucocorticoid replacement therapy); Patients with autoimmune diseases who do not require systematic treatment within two years can be enrolled;
6. Begin the study on subjects requiring systemic glucocorticoid therapy or other immunosuppressive therapy for a given condition within 14 days before treatment \[allowing subjects to use local, ocular, intra-articular, intranasal and inhaled glucocorticoid therapy (with very low systemic absorption); and allowing short-term (\< 7 days) glucocorticoid prophylaxis (e.g., contrast agent overdose) Sensitivity) or for the treatment of non-autoimmune diseases (e.g. delayed hypersensitivity caused by contact allergens), except for tumor reduction due to large tumor burden (prednisone 30mg, bid × 5 days or equivalent dose of other glucocorticoid therapy);
7. In the past five years, patients with other malignant tumors have undergone radical treatment, except for basal cell carcinoma of skin, squamous cell carcinoma of skin, carcinoma in situ of breast and carcinoma in situ of cervix;
8. Begin the study and receive systemic antineoplastic therapy within 28 days before treatment, including chemotherapy, immunotherapy, biotherapy (cancer vaccine, cytokines, or growth factors that control cancer), etc.;
9. The study began with AHST(Autologous Hemopoietic Stem Cell Transplantation) within 1month before treatment or Allo-HSCT(Allogeneic Hematopoietic Stem Cell Transplantation) within 3 months before treatment;
10. The study began with major surgery within 28 days before treatment or radiotherapy within 90 days before treatment;
11. Start the study and receive Chinese herbal medicine or Chinese 12.patent medicine treatment within 7 days before treatment;
12. Begin research on live vaccination (except influenza attenuated vaccine) within 28 days before treatment;
13. History of human immunodeficiency virus (HIV) infection and/or patients with acquired immunodeficiency syndrome are known;
14. Patients with active hepatitis B or active hepatitis C. Patients who are positive for hepatitis B Surface Antigen (HBsAg) or hepatitis C Virus (HCV) antibodies at screening stage must pass further detection of hepatitis B Virus (HBV) DNA titer (no more than 2500 copies/mL or 500 IU/mL) and HCV RNA (no more than the lower limit of the detection method) in the row. In addition to active hepatitis B or hepatitis C infections requiring treatment, group trials can be conducted. Hepatitis B carriers, stable hepatitis B (DNA titer should not be higher than 2500 copies/mL or 500 IU/mL) after drug treatment, and cured hepatitis C patients can be enrolled in the group; 19. Patients with active pulmonary tuberculosis;
15. Start studying any active infections requiring systemic anti-infective treatment within 14 days of treatment.
16. Pregnant or lactating women;
17. People with known history of alcoholism or drug abuse;
18. History of interstitial lung disease or non-infectious pneumonia. Subjects who had previously had non-infectious pneumonia caused by drugs or radiation but had no symptoms were allowed to enter the group;
19. Past psychiatric history; incapacitated or restricted;
20. According to the researchers' judgment, patients' underlying condition may increase their risk of receiving research drug treatment, or confuse their judgment on toxic reactions;
21. Other researchers consider it unsuitable for patients to participate in this study.