Efficacy and Safety Evaluation of IBI308 in Treatment of Patients With Relapsed/Refractory Classical Hodgkin's Lymphoma

Efficacy and Safety Evaluation of IBI308 in Treatment of Patients With Relapsed/Refractory Classical Hodgkin's Lymphoma: a Multicenter, Single Arm, Phase II Study

The study is to evaluate ORR, CR, PR DCR DOR PFS and safety of IBI308 in treatment of patients with Relapsed/Refractory Hodgkin's Lymphoma.

Patients with classical Hodgkin lymphoma(cHL) who relapse after autologous stem-cell transplantation(ASCT) or progress after multiple lines of chemotherapy have a poor prognosis, with a median survival of approximately 1.2 years.

CHL frequently harbors a spectrum of chromosome 9p24.1/PD-L1/PD-L2 alterations, leading to overexpression of the programmed death 1 ligands,PD-L1 and PD-L2.

Sintilimab is a humanized monoclonal antibody against PD-1 that blocks the interaction between PD-1 and its ligands and was approved for relapsed/refractory Hodgkin lymphoma in China in 2018.

This study is a single arm,phase 2 study designed to evaluate the clinical activity of sintilimab in Chinese patients with R/R

Inclusion Criteria:

1. Histopathological confirmed classical Hodgkin's lymphoma (cHL).

2. Relapsed/refractory cHL, which failed second line and above therapy (including radiotherapy and autologous hematopoietic stem cell transplantation, ASCT); subject with no response to or with progression after ASCT is eligible.

3. At least one measurable disease (long axis>15 mm or short axis>10 mm, with uptake on 18FDG-PET)

4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2.

5. Signed written informed consent form and willing and able to comply with scheduled visits and other requirements of the study.

6. Age ≥ 18.

7. Life expectancy of at least 12 weeks.

8. Subjects of reproductive potential must be willing to use adequate contraception during the course of the study and through 90 days after the last dose of study medication.

9. Adequate organ and bone marrow function:

   1. Count of Blood Cells: absolute neutrophil count (ANC) ≥ 0.75 × 109 / L; platelet count (PLT) ≥ 50 × 109 / L; hemoglobin content (HGB) ≥ 8.0 g / dL; no granulocyte colony-stimulating factor, platelet or red blood cells infusion in the last 14 days.
   2. Liver function: total bilirubin (TBIL) ≤ 1.5 × normal upper limit (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
   3. Renal function: serum creatinine (Cr) ≤ 1.5 × ULN.
   4. Thyroid function: thyroid stimulating hormone (TSH) in normal range (TSH abnormalities due to non-autoimmune causes can be enrolled).

Exclusion Criteria:

1. Known nodular lymphocyte predominant Hodgkin lymphoma.

2. Known central nervous system lymphoma.

3. Received ASCT within 90 days of the first dose of study medication.

4. Prior exposure to any anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody.

5. Currently participating in an interventional clinical study, unless participating in observational study or during follow-up period of an interventional study.

6. Received any investigational agent within 4 weeks of the first dose of study medication.

7. Received last dose of radiotherapy or anti-tumor therapy (chemotherapy, targeted therapy, tumor immunotherapy or arterial embolization) within 3 weeks of the first dose of study medication; received last dose of nitrosourea or mitomycin C within 6 weeks of the first dose of study medication.

8. Received systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 4 weeks of first dose. Inhaled or topical steroids and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease.

9. Received a live vaccine within 4 weeks of the first dose of study medication or plan to receive live vaccine during study period.

10. Underwent major operation (craniotomy, thoracotomy or laparotomy) within 4 weeks of the first dose of study medication or open wound, ulcer or fracture.

11. Activated, known or suspected autoimmune diseases or history of the disease with two years before enrollment. Vitiligo, psoriasis, hair loss, or Graves disease which do not need systemic treatment in 2 years, or hypothyroidism which only need thyroid hormone replacement therapy, or type-1 diabetes which only need insulin replacement therapy is eligible for enrollment.

12. Known primary immunodeficiency disorders.

13. Active tuberculosis.

14. Known history of allogeneic organ or allogeneic hemopoietic stem cell transplantation.

15. Known allergy or hypersensitivity to any monoclonal antibodies or any components used in their preparation.

16. Uncontrolled concomitant disease, including but not limited to :

    1. Human Immunodeficiency Virus (HIV) infection (HIV antibody positive)
    2. Active or poorly controlled severe infection
    3. Symptomatic congestive heart failure (New York Heart Association grade Ⅲ-IV) or symptomatic, poorly controlled arrhythmia
    4. Poorly controlled arterial hypertension (SBP ≥ 160mmHg or DBP ≥ 100mmHg) with standard treatment
    5. Prior arterial thromboembolism event, including myocardial infarction, unstable angina, stroke or transient ischemic attack, within 6 months before enrollment
    6. Prior life-threatening blood loss or grade 3/4 gastrointestinal/varicosity bleeding requiring blood infusion, endoscopic or surgical intervention within 3 months of enrollment
    7. Prior deep vein thrombosis, pulmonary embolism or any other severe thromboembolism events (implanted port or catheter caused thrombosis, or superficial vein thrombosis are not considered as severe thromboembolism events) within 3 months before enrollment
    8. History of uncontrolled metabolic disorder, non-malignant organ or systemic disease or secondary carcinomatous reaction, with high medical risk and/or uncertainty of survival evaluation
    9. With hepatic encephalopathy, hepato-renal syndrome or hepatic cirrhosis of Child-Pugh grade B or higher.
    10. History of intestinal obstruction or the following diseases: inflammatory bowel disease or extensive bowel resection (partial colonic resection or extensive small bowel resection, concomitant with chronic diarrhea), Crohn's disease, ulcerative colitis or chronic diarrhea
    11. Other acute or chronic diseases, mental illness, or abnormal laboratory test results that may lead to the following outcomes: increase the risk of participating in study or study drug administration, or interfere with the interpretation of the study results and considered by investigator as "NOT" eligible to participate in this study

17. Known acute or chronic active hepatitis B infection (chronic HBV carrier or non-active HBsAg positive subject is eligible) or acute or chronic active hepatitis C (HCV antibody negative subject is eligible; HCV RNA examination is required for HCV antibody positive subject, subject is eligible for enrollment if result was negative)

18. History of gastrointestinal perforation and /or fistula within 6 months before enrollment

19. Subjects with interstitial lung disease

20. Uncontrolled third space effusion, e.g. ascites or pleural effusion cannot be drained or controlled

21. Other primary malignancy, with the exception of:

    1. Curable malignancy (e.g. papillary thyroid carcinoma)
    2. Without active disease in the last 5 years and with very low recurrence risk
    3. Non-melanoma skin cancer or malignant freckle-like nevus with adequate treatment and no evidence of recurrence ;
    4. Adequately treated in-situ carcinoma

22. Women who are pregnant or in lactation period.